1-substituted-4-nitroimidazole compound and method for preparing the same

ABSTRACT

The present invention relates to a 1-substituted-4-nitroimidazole compound represented by the general formula (1) or a salt thereof, 
                         
(wherein R is a hydrogen atom, a lower alkoxy group-substituted lower alkyl group, a phenyl-lower alkoxy group-substituted lower alkyl group, a cyano-substituted lower alkyl group, a phenyl-lower alkyl group which may have lower alkoxy groups as the substituents in the phenyl ring or a group of the formula —CH 2 R A ; X is a halogen atom or a group of the formula —S(O)n-R 1 ) and method for preparing the same. The compound of the formula (1) is a useful compound as an intermediate for synthesis of various pharmaceutical and agricultural chemicals, particularly, as intermediates for antitubercular agents.

This is a continuation of application Ser. No. 10/523,008, filed Feb. 1,2005, U.S. Pat. No. 7,368,579 incorporated herein by reference, which isa 371 of PCT/JP03/13134, filed Oct. 14, 2003, incorporated herein byreference, which claims the benefit of Japan Application No. 2002-299896filed Oct. 15, 2002 and Japan Application No. 2003-37914 filed Feb. 17,2003.

TECHNICAL FIELD

The present invention relates to a 1-substituted-4-nitroimidazolecompound and method for preparing the same.

BACKGROUND ART

The 4-nitroimidazole compound and salt thereof represented by thegeneral formula (2),

[wherein, X is a halogen atom or a group of the formula —S(O)n-R¹; n is0 or an integer of 1 or 2; and R¹ is a phenyl group which may have 1 to3 substituents, selected from the group consisting of a nitro group, ahalogen atom and a lower alkyl group, in the phenyl ring],is a useful compound as intermediate for synthesis of variouspharmaceuticals and agricultural chemicals, particularly, asintermediates for preparing antitubercular agents.

Up to now, methods for preparing 4-nitroimidazole compound of thegeneral formula (2) are known, for example, methods shown by thefollowing Reaction scheme-1 and Reaction scheme-2. [Cf. Jerzy SUWINSKI,Ewa SALWINSKA, Jan WATRAS and Maria WIDEL, Polish Journal of Chemistry,56, 1261-1272, (1982)].

In the Reaction scheme-1 and -2, X^(A) is a halogen atom.

However, these methods involve several drawbacks, thus, they are notsuitable for industrially applicable methods of preparation. Forexample, in the method shown by Reaction scheme-1, compound (6) andcompound (7) as intermediates for the reaction are chemically unstablecompounds, thus these compounds are in danger of explosion caused byshocks of dropping, frictions and others. Further, in the reaction forintroducing compound (7) by heating (at about 130° C.) compound (6),this temperature exceeds TNR temperature (Temperature of No Return: anallowable maximum temperature around 60 to 70° C., at which the compound(6) can be handled safely in a chemical process equipment), for thisreason, this method involves very danger for conducting in a large scaleindustrial production of these objective compounds.

While, in the method shown by Reaction scheme-2, the reaction is anitration of a compound (8). However, by this nitration, the objectivecompound (2a) can be only obtained in low yield, thus this method isindustrially disadvantageous.

DISCLOSURE OF THE INVENTION

The present invention is directed to provide a1-substituted-4-nitroimidazole compound or a salt thereof and theprocess for preparing the same.

One object of the present invention is to provide a method for preparinga 4-nitroimidazole compound represented by the general formula (2a) ofhigh purity in high yield, by more safety method which brings lessdangers such as explosion and others. Another object of the presentinvention is to provide a novel 1-substituted-4-nitroimidazole compoundrepresented by the general formula (10) and a 4-nitroimidazole compoundsrepresented by the general formulas (2b) or (2c), those of which may beuseful as intermediates for preparing antitubercular agents.

The present inventors have intensively conducted research works todevelop for the purpose to achieve the above-mentioned objectives, thatprovide methods for preparing a 4-nitroimidazole compound represented bythe general formula (2a) and a novel 1-substituted-4-nitroimidazolecompound which can be used as intermediates for preparing antitubercularagents. As the results, the present inventors have found that theabove-mentioned objectives can be achieved, by the use of a4-nitroimidazole compound represented by the general formula (3), a4-nitroimidazole compound represented by the general formula (4), a4-nitroimidazole compound represented by the general formula (25), a1-nitroimidazole compound represented by the general formula (26), a1-substituted-4-nitroimidazole compound represented by the generalformula (10) or a 4-nitroimidazole compound represented by the generalformula (2b) or (2c) as the intermediates, and a nitration of animidazole compound represented by the general formula (15) by novelmethod.

Thus, according to the research works made by the present inventors, wehave found the facts that:

1) by removing R^(A′)-group from a 1-substituted-4-nitroimidazolecompound represented by the general formula (1a), obtained by reducing a4-nitroimidazole compound represented by the general formula (3), 2) byreducing a 4-nitroimidazole compound represented by the general formula(4), or 3) by nitrating imidazole compound represented by the generalformula (15) by novel method; a 4-nitroimidazole compound represented bythe general formula (2a) with high purity can be prepared in high yield,by more safety method which brings less dangers.

Further, the present inventors have found the fact that, a1-substituted-4-nitroimidazole compound represented by the generalformula (1) formed on the way of this method is a novel compound whichhas not been known before in any literature.

The present invention has been successfully completed on the basis ofthe above mentioned findings and knowledges. Thus, the present inventionis explained as follows:

1) The present invention relates to a 1-substituted-4-nitroimidazolecompound represented by the general formula (1),

[wherein R is a hydrogen atom, a lower alkoxy group-substituted loweralkyl group, a phenyl-lower alkoxy group-substituted lower alkyl group,a cyano group-substituted lower alkyl group, a phenyl-lower alkyl groupwhich may have a lower alkoxy group as the substituents in the phenylring, or a group of the formula —CH₂R^(A); R^(A) is a group of thefollowing formula,

wherein R^(B) is a hydrogen atom or a lower alkyl group; X shows ahalogen atom or a group of the formula —S(O)n-R¹; n is 0 or an integerof 1 or 2; and R¹ is a phenyl group which may have 1 to 3 substituents,selected from the group consisting of a nitro group, a halogen atom anda lower alkyl group, in the phenyl ring; provided that when X is ahalogen atom, then R should not be a hydrogen atom], or a salt thereof.2) The present invention relates to a method for preparing a4-nitroimidazole compound represented by the general formula (2a),

[wherein, X^(A) is a halogen atom],which is characterized by reducing a 4-nitroimidazole compoundrepresented by the general formula (3),

[wherein R^(A′) is a lower alkoxy group-substituted lower alkyl group, aphenyl-lower alkoxy group-substituted lower alkyl group, a cyanogroup-substituted lower alkyl group, a phenyl-lower alkyl group whichmay have a lower alkoxy group as the substituent in the phenyl ring;X^(A) and X¹ are each a halogen atom]and removing the R^(A′) group from the obtained1-substituted-4-nitroimidazole compound represented by the generalformula (1a),

[wherein R^(A′) and X^(A) are the same as defined above]3) The present invention relates to method for preparing a4-nitroimidazole compound represented by the general formula (2a),

[wherein X^(A) is the same as defined previously],which is characterized by reducing a 4-nitroimidazole compoundrepresented by the general formula (4),

[wherein X^(A) and X¹ are the same as defined previously].4) The present invention relates to a method for preparing a1-substituted-4-nitroimidazole compound represented by the generalformula (10),

[wherein R^(A) and X are the same as defined previously], which ischaracterized by reacting a 4-nitroimidazole compound represented by thegeneral formula (2),

[wherein X is the same as defined previously], with a glycidylbenzenesulfonate represented by the general formula (11),

[wherein R^(A) is a group of the following formula

wherein R^(B) is a hydrogen atom or a lower alkyl group; andR^(C) is a group of the formula,

wherein R^(D) is a nitro group; R^(E) is a halogen atom or a lower alkylgroup; a is 0, or an integer of 1 or 2; provided that when a is 2, thentwo of R^(E) may be the same or different].5) The present invention relates to a method for preparing a4-nitroimidazole compound represented by the general formula (2b) or(2c),

[wherein R¹ and n are the same as defined previously], which ischaracterized by removing R^(A′) group from a1-substituted-4-nitroimidazole compound represented by the generalformula (25) or (25a),

[wherein R^(A′), n and R¹ are the same as defined previously]6) The present invention relates to a method for preparing a4-nitroimidazole compound represented by the general formula (2b),

[wherein R¹ is the same as defined previously], which is characterizedby rearranging a 1-nitroimidazole compound represented by the generalformula (26),

[wherein R¹ are the same as defined previously].7) The present invention relates to a method for preparing a4-nitroimidazole compound represented by the general formula (25a), (2c)or (10d),

[wherein R¹ and R are the same as defined previously: n₁ is an integerof 1 or 2],which is characterized by oxidizing a 4-nitroimidazole compoundrepresented by the general formula (25), (2b) or (10c),

[wherein R¹ and R are the same as defined previously].8) The present invention relates to a method for preparing a4-nitroimidazole compound represented by the general formula (15a),

[wherein X¹ is the same as defined previously], which is characterizedby nitrating an imidazole compound represented by the general formula(15),

[wherein X¹ is the same as defined previously]in the presence of a nitronium halogenated borate.9) The present invention relates to a process for preparing the4-nitroimidazole compound as mentioned in the above item 8), wherein thenitronium halogenated borate is nitronium tetrafluoroborate.10) The present invention relates to a method for preparing4-nitroimidazole compound as mentioned in the above item 9), wherein thenitration is conducted in nitromethane.11) The present invention relates to a method for preparing a1-substituted-4-nitroimidazole compound represented by the generalformula (10c),

[wherein R¹ and R^(A) are the same as defined previously], which ischaracterized by nitrating a 1-substituted imidazole compoundrepresented by the general formula (27),

[wherein R¹ and R^(A) are the same as defined previously].12) The present invention relates to a 4-nitroimidazole derivativerepresented by the general formula (41),

[wherein, X^(B) is a bromine atom, or a group of —S(O)nR¹ (wherein R¹and n are the same as defined previously); R^(J) is a group of theformula,

(wherein R^(K) and R^(L) are each, respectively a tetrahydropyranylgroup, a tri(lower alkyl)silyl group, a lower alkanoyl group, aphenyl-lower alkyl group which may have a lower alkoxy groups as thesubstituents in the phenyl ring or a hydrogen atom)] or a salt thereof.13) The present invention provides(S)-2-bromo-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole or a saltthereof.14) The present invention provides(R)-2-bromo-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole or a saltthereof.15) The present invention provides(S)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole or a saltthereof.16) The present invention provides(R)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole or a saltthereof.

MODE FOR CARRYING OUT OF THE INVENTION

In the present invention, 1-substituted-4-nitroimidazole compounds ofthe general formula (1) and 1-substituted-4-nitroimidazole compounds ofthe general formula (10) are novel compounds which have not been knownin any literature.

1-Substituted-4-nitroimidazole compounds of the general formula (1) areuseful as intermediates for synthesis of various pharmaceuticals andagricultural chemicals, particularly, as intermediates for synthesis of4-nitroimidazole compounds of the general formula (2) being useful asintermediates for preparing antitubercular agents. Further,1-substituted-4-nitroimidazole compounds of the general formula (10) areuseful as intermediates for preparing antitubercular agents.

Each of groups shown in the above mentioned general formula (1) arespecifically explained as follows.

As to the halogen atoms, a fluorine atom, chlorine atom, bromine atomand iodine atom can be exemplified.

As to the lower alkoxy group-substituted lower alkyl group, a straightchain or branched chain alkyl group having 1 to 6 carbon atoms, in which1 to 2 straight chain or branched chain alkoxy group having 1 to 6carbon atoms are substituted, for example, methoxymethyl,3-methoxypropyl, ethoxymethyl, diethoxymethyl, dimethoxymethyl,1-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoxypentyl,6-(n-propoxy)hexyl, 1,1-dimethyl-2-butoxyethyl,2-methyl-3-tert-butoxypropyl, 2-(n-pentyloxy)ethyl, n-hexyloxymethylgroups and the like can be exemplified.

As to the phenyl-lower alkoxy group-substituted lower alkyl group, astraight chain or branched chain alkyl group having 1 to 6 carbon atoms,in which the phenylalkoxy group wherein the alkoxy moiety is a straightchain or branched chain alkoxy group having 1 to 6 carbon atoms, issubstituted, for example, benzyloxymethyl, (2-phenylethoxy)methyl,(1-phenylethoxy)methyl, 3-(3-phenylpropoxy)propyl,4-(4-phenylbutoxy)butyl, 5-(5-phenylpentyloxy)pentyl,6-(6-phenylhexyloxy)hexyl, 1,1-dimethyl-(2-phenylethoxy)ethyl,2-methyl-3-(3-phenylpropoxy)-propyl, 2-benzyloxyethyl, 1-benzyloxyethyl,3-benzyloxypropyl, 4-benzyloxybutyl, 5-benzyloxypentyl, 6-benzyloxyhexylgroups and the like can be exemplified.

As to the phenyl-lower alkyl group which may have straight chain orbranched chain alkoxy groups as substituents in the phenyl ring, aphenylalkyl group wherein the alkyl moiety is a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms, and the phenylring may have 1 to 3 straight chain or branched chain alkoxy groupshaving 1 to 6 carbon atoms, for example, benzyl, 2-phenylethyl,1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl,4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl,3,4,5-trimethoxybenzyl, 2-(4-ethoxyphenyl)ethyl,1-(3-propoxyphenyl)ethyl, 3-(2-butoxyphenyl)propyl,4-(4-pentyloxyphenyl)butyl, 5-(4-hexyloxyphenyl)pentyl,6-(2,4-diethoxyphenyl)hexyl,1,1-dimethyl-2-(3-methoxy-4-ethoxyphenyl)ethyl,2-methyl-3-(2-methoxy-6-propoxyphenyl)propyl groups and the like can beexemplified.

As to the cyano-substituted lower alkyl group, a cyanoalkyl groupwherein the alkyl moiety is a straight chain or branched chain alkylgroup having 1 to 6 carbon atoms, for example, cyanomethyl,2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl,6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl, 2-methyl-3-cyanopropyl groupsand the like can be exemplified.

As to the phenyl group which may have 1 to 3 substituents selected fromthe group consisting of a nitro group, a halogen atom and a lower alkylgroup in the phenyl ring, a phenyl group which may have 1 to 3substituents selected from the group consisting of a nitro group, ahalogen atom and a straight chain or branched chain alkyl group having 1to 6 carbon atoms in the phenyl ring, for example, phenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl,4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl,2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,4,5-trimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl,3,4-dinitrophenyl, 2,4-dinitrophenyl, 2,5-dinitrophenyl,2,6-dinitrophenyl, 3,4,5-trinitrophenyl, 4-fluorophenyl,2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl,3-fluorophenyl, 2-fluorophenyl, 4-iodophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 3,5-dichlorophenyl, 2,4,6-trifluorophenyl,2-iodophenyl, 3-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl,2,4,6-trichlorophenyl, 2-chloro-4-nitrophenyl, 3-nitro-4-methylphenyl,3-ethyl-2-nitrophenyl, 2-fluoro-4-nitro-6-methylphenyl groups and thelike can be exemplified.

As to the lower alkyl group, a straight chain or branched chain alkylgroup having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl groups canbe exemplified.

In the 1-substituted-4-nitroimidazole compounds represented by thegeneral formula (10) of the present invention, the compounds representedby the general formula (10a) and (10b) are involved.

Method for preparing a 4-nitroimidazole compound of the general formula(2) of the present invention is explained as follows.

The 4-nitroimidazole compound of the general formula (2) is prepared bythe following Reaction scheme-3.

[wherein, R^(A′), X^(A) and X¹ are the same as defined above; X² is ahalogen atom or a lower alkoxy group.

As to the lower alkoxy group, a straight chain or branched chain alkoxygroup having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, n-hexyloxygroup and the like can be exemplified, and particularly, methoxy groupand ethoxy group are preferable.

In the above Reaction scheme-3, the reaction of obtaining compound (4)from compound (5) can be carried out in a suitable solvent and in thepresence of a halogenating agent.

As to the halogenating agents to be used in the reaction, for example,halogen molecules such as bromine, chlorine, iodine and the like, iodinechloride, sulfuryl chloride, copper compounds such as copper(II)bromide, N-halogenated succinimides such as N-bromosuccinimide,N-chlorosuccinimide and the like, halogenated alkanes such ashexachloroethane and the like can be exemplified. The halogenating agentmay be used, generally in an equimolar to 10 times molar quantity,preferably in an equimolar to 5 times molar quantity per one molarquantity of compound (5).

As to the solvents, for example, water; halogenated hydrocarbons, suchas dichloromethane, dichloroethane, chloroform, carbon tetrachloride andthe like; ethers such as tetrahydrofuran, diethyl ether, dioxane,di(ethylene glycol) dimethyl ether, dimethoxyethane and the like;aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; fattyacids such as acetic acid, propionic acid, and the like; carbondisulfide and the like; and mixtures of these solvents and the like canbe exemplified.

In carrying out of the reaction, an inorganic base, such as sodiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumhydroxide, potassium carbonate, potassium hydrogencarbonate or the like;an alkyl lithium such as n-butyl lithium may be added in the reactionsystem.

The reaction is carried out, generally at −50 to 150° C., preferably at−50 to 100° C., for about 5 minutes to 10 hours.

In the reaction of compound (4) with compound (9), when X² is a halogenatom, then the reaction is conducted in a suitable solvent and in thepresence or absence of the basic compound.

As to the solvents to be used in the reaction, aromatic hydrocarbonssuch as benzene, toluene, xylene and the like; ethers such as diethylether, tetrahydrofuran, dioxane, di(ethylene glycol) dimethyl ether,dimethoxyethane and the like; halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride; loweralcohols such as methanol, ethanol, isopropanol, n-butanol, tert-butanoland the like; acetic acid; esters such as ethyl acetate, methyl acetate,n-butyl acetate and the like; ketones such as acetone, methylethylketone and the like; acetonitrile, pyridine, 2,4,6-collidine, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidinone (NMP), hexamethylphosphorous triamide; andmixtures of these solvents and the like can be exemplified.

As to the basic compounds, inorganic bases, for example, metalcarbonates such as sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate and the like; metalhydroxides such as sodium hydroxide, potassium hydroxide, calciumhydroxide and the like; and sodium hydride, potassium, sodium, sodiumamide; metal alcoholates such as sodium methylate, sodium ethylate andthe like; and organic bases, for example, pyridine, 2,4,6-collidine,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like can beexemplified.

The amount of the basic compound may be, generally 1 to 5 molarquantities per 1 mole of compound (4).

The amount of compound (9) may be, generally at least an equimolarquantity, preferably 1 to 5 molar quantities per 1 mole of compound (4).

The reaction is carried out, generally at about −50 to 200° C.,preferably at about −50 to 150° C., and generally for about 1 to 30hours. An alkali metal halides such as sodium iodide or the like may beadded in the reaction system.

In the reaction of compound (4) with compound (9), when X² is a loweralkoxy group, under the above mentioned reaction condition, an acid, forexample, sulfonic acid such as camphorsulfonic acid or p-toluenesulfonicacid may be used in place of the basic compound.

The amount of the acid may be, generally a catalytic amount, preferably,0.01 to 0.2 molar quantity per 1 mole of compound (4).

The reaction for obtaining compound (1a) from compound (3) and thereaction for obtaining compound (2a) from compound (4) are carried outin a suitable solvent and in the presence of a reducing agent.

As to the reducing agent to be used in the reaction, for example, metalsulfite such as sodium sulfite, sodium hydrogensulfite and the like;tetra-lower alkyl ammonium borohydrides such as tetramethyl ammoniumborohydride, tetraethyl ammonium borohydride, tetra-n-butyl ammoniumborohydride, tetra-n-butyl ammonium cyanoborohydride and the like;hydride reducing agents such as sodium cyanoborohydride, lithiumcyanoborohydride, sodium borohydride, diborane and the like can beexemplified.

As to the solvents to be used in the reaction, for example, water, loweralcohols such as methanol, ethanol, isopropanol and the like, ketonessuch as acetone, methyl ethyl ketone and the like, ethers such asdiethyl ether, tetrahydrofuran, diisopropyl ether, diglyme, 1,4-dioxane,dimethoxyethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, dimethyl sulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone (NMP), and mixtures ofthese solvents and the like can be exemplified.

In the case that diborane is used as the reducing agent, an anhydroussolvent may be preferably used.

The amount of the reducing agent is generally at least an equimolarquantity, preferably about 1 to 10 molar quantities per 1 mole ofcompound (3) or compound (4).

The reaction is carried out, generally at about 0 to 150° C., preferablyat about 0 to 120° C., and is finished in about 1 to 30 hours.

Compound (1a) or (2a) can be obtained by the reaction in a suitablesolvent, which is carried out by using a reducing agent, for example, acatalytic hydrogenation reducing agent, such as palladium,palladium-black, palladium-carbon, palladium hydroxide-carbon,rhodium-alumina, platinum, platinum oxide, copper chromite, Raneynickel, palladium acetate and the like; and a fatty acid, an ammoniumsalt of fatty acid or an alkali metal salt of fatty acid, such as formicacid, sodium formate, ammonium formate, sodium acetate and the like,under the reaction temperature of, generally a room temperature to 200°C., preferably a room temperature to 150° C., for about 1 to 30 hours.

The solvent to be used in this reaction is any solvent which is capableto be used in the reduction with using the above-mentioned catalytichydrogenation reducing agent. In this reaction, amines such astriethylamine and the like, and phosphorous compounds such astri-ortho-tolylphosphine and the like may be added.

The amount of the catalytic hydrogenation reducing agent may be,generally about 0.1 to 40% by weight, preferably 0.1 to 20% by weightper 1 mole of compound (3) or compound (4). The amount of the fattyacid, ammonium salt of fatty acid or metal salt of fatty acid may be,generally at least an equimolar quantity, preferably about 1 to 20 molarquantity per 1 mole of compound (3) or compound (4).

The reaction can be carried out, in a suitable solvent, by reducing thecompound (3) or compound (4) in the presence of the catalytichydrogenation reducing agent. As to the solvent to be used in thereaction, for example, water; fatty acids such as acetic acid and thelike; alcohols such as methanol, ethanol, isopropanol and the like;aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, monoglyme,diglyme, dimethoxyethane and the like; esters such as ethyl acetate,methyl acetate, n-butyl acetate and the like; aprotic solvents such asN,N-dimethylformamide N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone(NMP) and the like; and mixtures of these solvents can be exemplified.As to the catalytic hydrogenation reducing agent, for example palladium,palladium acetate, palladium-black, palladium-carbon, palladiumhydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copperchromite, Raney nickel and the like can be exemplified. The amount ofthe catalytic hydrogenation reducing agent is, generally about 0.02 to 1part by weight per 1 mole of compound (3) or compound (4). The reactiontemperature may be, generally at about −20 to 100° C., preferably, atabout 0 to 80° C., and hydrogen pressure may be, generally about 1 to 10atmospheric pressure. The reaction is generally finished about 0.5 to 20hours. The reaction is proceeded advantageously by adding amines such astriethylamine to the reaction system.

Compound (1a) or compound (2a) can be obtained by reacting, in asuitable solvent, in the presence of a catalyst, generally at a roomtemperature to 200° C., preferably at a room temperature to 150° C., forabout 1 to 10 hours. As to the solvent to be used in the reaction, anysolvent to be used in the above-mentioned reduction with thehydrogenation reducing agent can be also used. As to the catalyst,palladium compounds such as palladium acetate-triphenylphosphine,tetrakis(triphenylphosphine)palladium and the like can be exemplified.The amount of the catalyst may be about 0.01 to 5 molar quantities,preferably about 0.01 to an equimolar quantity per 1 mole of compound(3) or compound (4). The reaction is advantageously proceeded by addingan alkyl silane compound such as triethyl silane to the reaction system.

In accordance with this reducing reaction, the desired compound of thegeneral formula (1a) or (2a) wherein, 5-position of imidazole ring isselectively dehalogenated can be obtained, this fact has been firstlyfound by the present inventors.

The reaction for obtaining compound (2a) from compound (1a) can becarried out in a suitable solvent or without a solvent, in the presenceof a basic compound or acid compound.

As to the solvents to be used in this reaction, for example, water;lower alcohols such as, methanol, ethanol, isopropanol and the like;ketones such as acetone, methyl ethyl ketone and the like; ethers suchas diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethylether, dimethoxyethane and the like; esters such as ethyl acetate,methyl acetate, n-butyl acetate and the like; fatty acids such as aceticacid, formic acid and the like; N,N-dimethylacetamide,1-methyl-2-pyrrolidinone (NMP) and mixtures of these solvents and thelike can be exemplified.

As to the basic compounds, those of well-known can be used widely. Anyone of the basic compounds used in the reaction of compound (4) withcompound (9), when X² is a halogen atom, can be used.

As to the acids, those of well-known can be used widely, for example,mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acidand the like; formic acid, acetic acid, trifluoroacetic acid; aromaticsulfonic acids such as p-toluenesulfonic acid can be exemplified.

The reaction is generally carried out at about 0 to 150° C., preferablyat about 0 to 100° C., and is generally finished for about 5 minutes to30 hours.

In case of using an acid in this reaction, anisol and the like may beadded to the reaction system.

1-Substituted-4-nitroimidazole compound represented by the generalformula (10) is prepared for example by the following Reaction scheme-4.

[wherein, R^(A), R^(c) and X are the same as defined above].

The reaction of 4-nitroimidazole compound represented by the generalformula (2) with compound (11) is carried out in a suitable solvent, inthe presence of a basic compound.

As to the solvent to be used in the reaction, for example, aromatichydrocarbons such as benzene, toluene, xylene, o-chlorobenzene,m-chlorobenzene, 2,3-dichlorobenzene and the like; ethers such asdiethyl ether, tetrahydrofuran, dioxane, di(ethylene glycol) dimethylether, dimethoxyethane and the like; halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride andthe like; lower alcohols such as methanol, ethanol, isopropanol,butanol, tert-butanol and the like; acetic acid; esters such as ethylacetate, methyl acetate, n-butyl acetate and the like; ketones such asacetone, methyl ethyl ketone and the like; acetonitril, pyridine,1-methyl-2-pyrrolidinone (NMP), 2,4,6-collidine, dimethyl sulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoroustriamide; and mixtures of these solvents and the like can beexemplified.

As to the basic compound, well-known inorganic bases and organic basescan be widely used.

As to the inorganic bases, for example, alkali metal carbonates such assodium carbonate, potassium carbonate and the like; alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide and the like; alkali metal phosphatessuch as sodium phosphate, potassium phosphate and the like; alkali metalhydrides such as sodium hydride, potassium hydride and the like; alkalimetals such as potassium, sodium and the like; alkali metal amides suchas sodium amide and the like; alkali metal alcoholate such as sodiummethylate, sodium ethylate and the like can be exemplified.

As to the organic bases, for example, pyridine, trimethylamine,triethylamine, N-ethyldiisopropylamine, 2,4,6-collidine,dimethylaniline, dimethylaminopyridine, N-methylmorphorine,N,N-dimethyl-4-aminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like can be exemplified.

These basic compounds are used singly or by mixing two or more thereof.

The amount of compound (2) is generally about 0.1 to 5 molar quantities,preferably about 0.5 to 3 molar quantities per 1 mole of compound (11).The amount of the basic compound is generally 1 to 10 molar quantities,preferably 1 to 5 molar quantities per 1 mole of compound (11).

The reaction of compound (2) with compound (11) is carried out generallyat about 0 to 150° C., preferably at about 0 to 100° C., and generallythe reaction is finished in about 1 to 100 hours.

In the above-mentioned reaction, a halide compound such as cesiumfluoride may added in the reaction system.

More specifically, 1-substituted-4-nitroimidazole compound representedby the general formula (10a) is prepared by the reaction of compound (2)with compound (11a) as shown in the following reaction scheme, and1-substituted-4-nitroimidazole compound represented by the generalformula (10b) is prepared by the reaction of compound (2) with compound(11b) as shown in the following reaction schemes.

In the above-mentioned reaction, compound (2) to be used as the startingmaterial is prepared, for example, by the above-mentioned Reactionscheme-2, Reaction scheme-3 or Reaction scheme-8 mentioned below.

On the other hand, compound (11) [compound (11a) or compound (11b)] tobe used as another starting material is prepared from well-knowncompound (12) by the following Reaction scheme-5.

[wherein, R^(B), R^(C) and X¹ are the same as defined previously].

Compound (11a) is prepared by oxidizing compound (12), and the thusobtained oxidized compound is reacted with compound (13).

Oxidation of compound (12) is carried out in a suitable solvent, in thepresence of a dextrorotary optically active compound by using as anoxidizing agent.

As to the oxidizing agent to be used in the reaction, well-knownperoxides can be used widely, for example, cumene hydroperoxide,tert-butyl peroxide and the like can be exemplified.

As to the solvents, for example, alcohols such as methanol, ethanol,isopropanol and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride andthe like; ethers such as diethyl ether, dioxane, tetrahydrofuran,diglyme, dimethoxyethane and the like; saturated hydrocarbons such asn-hexane, n-butane, cyclohexane and the like; ketones such as acetone,methyl ethyl ketone and the like; polar solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone(NMP), dimethyl sulfoxide, hexamethylphosphorous triamide, acetonitrileand the like; and mixtures of these solvents can be exemplified.

As to the dextrorotary optically active compounds, for example,dextrorotary optically active acids or their alkyl esters, such asdiisopropyl(D)-(−)-tartrate, (D)-(−)-tartaric acid,(D)-(−)-di-p-toluoyltartaric acid, (D)-(−)-malic acid, (D)-(−)-mandelicacid, (D)-(−)-camphor-10-sulfonic acid and the like can be exemplified.

The amount of the oxidizing agent is generally at least an equimolarquantity, preferably about 1 to 3 molar quantity per 1 mole of compound(12).

The amount of the dextrorotary optically active compound is generallyabout 0.01 to 1 molar quantity, preferably about 0.01 to 0.5 molarquantity per 1 mole of compound (12).

The oxidation of compound (12) is generally carried out at about −50° C.to a room temperature, preferably at about −30° C. to a roomtemperature, and is finished in about 1 to 30 hours.

In conducting the oxidation of compound (12), an agent for acceleratingreaction may preferably be added to the reaction system. As to the agentfor accelerating reaction, for example, alkoxy titanium such as titaniumtetraisopropoxide and the like; molecular sieves such as molecularsieves 5A, molecular sieves 4A, molecular sieves 3A and the like can beexemplified. These agents are used singly or by mixing two or more ofthese agents. The amount of the alkoxy titanium is generally about 0.01to 1 molar quantity, preferably 0.01 to 0.5 molar quantity per 1 mole ofcompound (12). The amount of the molecular sieves is generally about 0.1to 1 part by weight against 1 part by weight of compound (12).

The reaction of compound [compound (14a)] obtained by theabove-mentioned oxidation with compound (13) is carried out in asuitable solvent, in the presence of a basic compound.

As to the solvent to be used in this oxidation, any one of the solventsused in the oxidation of compound (12) can be used.

As to the basic compounds, well-known inorganic bases and organic basescan be used.

As to the inorganic bases, for example, alkali metal carbonates such assodium carbonate, potassium carbonate and the like; alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide and the like; alkali metal phosphatessuch as sodium phosphate, potassium phosphate and the like; alkali metalhydrides such as sodium hydride, potassium hydride and the like; alkalimetals such as potassium, sodium and the like; alkali metal amides suchas sodium amide and the like; alkali metal alcoholates such as sodiummethylate, sodium ethylate, and the like can be exemplified.

As to the organic bases, for example, pyridine, trimethylamine,triethylamine, N-ethyldiisopropylamine, 2,4,6-collidine,dimethylaniline, dimethylaminopyridine, N-methylmorpholine,N,N-dimethyl-4-aminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like can be exemplified.

These basic compounds are used singly or by mixing two or more of these.

The amount of compound (13) is generally about at least 1 mole,preferably about 1 to 2 moles per 1 mole of compound (12).

The amount of the basic compound is generally about at least 1 mole,preferably 1 to 2 moles per 1 mole of compound (12).

The reaction of compound (14a) with compound (13) is carried out,generally at −50° C. to about a room temperature, preferably at −30° C.to about a room temperature, and is finished generally in 1 to 20 hours.

In the present invention, the desired compound (11a) can be prepared inthat, after the oxidation of the compound (12), the reaction mixture isreacted with compound (13) without being separated the obtained compound(14a) from the reaction system. From view points of the workability andefficiency of the reaction, it is preferable to react compound (13) withthe reaction mixture after the oxidation of the compound (12), since thesolvents used in these series of reactions are the same.

Compound (11b) is prepared, at first by oxidizing compound (12), nextthe compound obtained by oxidation is reacted with compound (13).

Oxidation of compound (12) is carried out under the reaction conditionsimilar to the oxidation of the above-mentioned compound (12), exceptthat by using a levorotatory optically active compound in place of byusing dextrorotatory optically active compound.

As to the levorotatory optically active compounds for example,levorotatory optically active acids or their alkyl esters, such asdiisopropyl(L)-(+)-tartarate, (L)-(+)-tartaric acid,(L)-(+)-di-p-toluoyltartaric acid, (L)-(+)-malic acid, (L)-(+)-mandelicacid, (L)-(+)-camphor-10-sulfonic acid and the like can be exemplified.

Reaction of compound (14a), which is obtained from the above-mentionedoxidation, with compound (13) is carried out in a suitable solvent, inthe presence of a basic compound.

Reaction of compound (14b) with compound (13) is carried out under thereaction condition similar to that of employed in the reaction ofcompound (14a) with compound (13).

In the present invention, the desired compound (11b) can be prepared inthat, after the oxidation of the compound (12), the reaction mixture isreacted with compound (13) without being separated the obtained compound(14b) from the reaction system. From view points of the workability andefficiency of the reaction, it is preferable to react compound (13) withthe reaction mixture after the oxidation of the compound (12), since thesolvents used in these series of reactions are the same.

Compound (4) in the above-mentioned Reaction scheme-3 can also beprepared by the following Reaction scheme-6.

[wherein, X¹ is the same as defined in the above; X³ and X⁴ are eachshows a halogen atom].

Reaction of introducing compound (15) to compound (16) can be carriedout under the condition similar to that employed in the reaction ofobtaining compound (4) from compound (5) in Reaction scheme-3 mentionedpreviously.

Reaction of obtaining compound (17) from compound (16) can be carriedout under the condition similar to that employed in the reaction ofobtaining compound (1a) from compound (3) and the reaction of obtainingcompound (4) from compound (2a) in Reaction scheme-3 mentionedpreviously.

Reaction of obtaining compound (4a) from compound (16) or compound (17)can be carried out under the condition similar to that employed in thenitration of an aromatic compound in general. For example, the reactionis carried out in a solvent or without solvent, in the presence of anitrating agent. As to the solvent to be used in this nitration, fattyacids or anhydrides thereof such as acetic acid, acetic anhydride andthe like; inorganic acids such as concentrated sulfuric acid and thelike; halogenated hydrocarbons such as chloroform, dichloromethane,carbon tetrachloride and the like; and nitromethane and the like can beexemplified. As to the nitrating agents, for example, fuming nitricacid, concentrated nitric acid, mixed acid (a mixture of sulfuric acid,fuming sulfuric acid, phosphoric acid or acetic anhydride with nitricacid); a mixture of an alkali metal nitrate such as potassium nitrate,sodium nitrate and the like with sulfuric acid; alkyl ammonium nitratessuch as tetra-n-butylammonium nitrate and the like; nitronium haloboratesuch as nitronium tetrafluoroborate and the like can be exemplified.

The amount of the nitrating agent may be at least an equimolar quantity,generally an excess amount of the agent is used per 1 mole of compound(1.6) or (17). In case of using alkylammonium nitrates or nitroniumhaloborates, at least an equimolar quantity, preferably an equimolarquantity to about 5 molar quantities may be used per 1 mole of compound(16) or (17). The said reaction is generally finished at −30° C. toabout a room temperature, in about 10 minutes to 20 hours. In case ofusing an alkylammonium nitrate as the nitrating agent, at least anequimolar quantity, preferably an equimolar to 3 molar quantities of thefatty acid anhydride such as trifluoroacetic anhydride is used per 1mole of compound (16) or (17) in the reaction system.

The starting material of compound (15) is a well-known compound, and canbe also prepared by method of the following Reaction scheme-7.

[wherein, X¹, X² and R^(A′) are the same as defined previously].

Reaction of compound (18) with compound (9) can be carried out under thecondition similar to that employed in the reaction of compound (4) withcompound (9) in the above-mentioned Reaction scheme-3.

Reaction of obtaining compound (20) from compound (19) can be carriedout under the condition similar to that employed in the reaction ofobtaining compound (4) from compound (5) in the above-mentioned Reactionscheme-3.

Reaction of obtaining compound (15) from compound (20) can be carriedout under the condition similar to that employed in the reaction ofobtaining compound (2a) from compound (1a) in the above-mentionedReaction scheme-3.

4-Nitroimidazole compound of the general formula (2) can also beprepared by the following Reaction scheme-8.

[wherein, R^(A′), R¹ and X² are the same as defined in the above; n₁shows 1 or 2: X⁵ shows a halogen atom].

Reaction of compound (21) with compound (22) and reaction of compound(23) with compound (9) can be carried out under the condition similar tothat employed in the reaction of compound (4) with compound (9) in theabove-mentioned Reaction scheme-3. Further, compound (24) can beprepared by reacting compound (23) with acrylonitrile. This reaction canbe carried out in a suitable solvent or without solvent, in the presenceof a basic compound. The solvent and the basic compound used in thisreaction are any one of those used in the reaction of compound (4) withcompound (9) in the above-mentioned Reaction scheme-3. The amount ofacrylonitrile may be at least an equimolar quantity, preferably anequimolar to about 15 molar quantities per 1 mole of compound (23). Thesaid reaction is carried out generally at 0 to 150° C., preferably atabout 0 to 100° C., and is finished generally in about 10 minutes to 5hours.

Reaction of obtaining compound (25) from compound (24) and reaction ofobtaining compound (26) from compound (23) can be carried out under thecondition similar to that employed in the reaction of obtaining compound(4a) from compound (16) or (17) in the above-mentioned Reactionscheme-6.

In carrying out the reaction of obtaining compound (25) from compound(24), simultaneously compound (25aa), wherein the nitro group issubstituted in the 5-position of the imidazole skeleton, is obtained.The compound (2b) can be obtained from the compound (25aa) under thecondition similar to that employed in the reaction of obtaining compound(2b) from compound (25).

Reaction of obtaining compound (2b) from compound (25) and reaction ofobtaining compound (2c) from compound (25aa) can be carried out underthe condition similar to that employed in the reaction of obtainingcompound (2a) from compound (1a) in the above-mentioned Reactionscheme-3.

Reaction of obtaining compound (2b) from compound (26) can be carriedout by heating in a suitable solvent. As to the solvent to be used inthis reaction, aromatic hydrocarbons such as toluene, xylene, benzene,chlorobenzene and the like can be exemplified. The said reaction isgenerally carried out at a room temperature to 200° C., preferably atabout a room temperature to 150° C., and reaction time is generallyfinished in about 10 minutes to 5 hours.

Reaction of obtaining compound (2c) from compound (2b) and reaction ofobtaining compound (25a) from compound (25) are carried out in asuitable solvent, in the presence of an oxidizing agent. As to thesolvent to be used in this reaction, for example, water; fatty acidssuch as formic acid, acetic acid, trifluoroacetic acid and the like;lower alcohols such as methanol, ethanol, isopropanol, n-butanol,tert-butanol, and the like; halogenated hydrocarbons such as chloroform,dichloromethane, carbon tetrachloride and the like; and mixtures ofthese solvent can be exemplified. As to the oxidizing agent to be used,for example, peracids such as performic acid, peracetic acid,pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid,o-carboxyperbenzoic acid and the like; hydrogen peroxide; sodiummetaperiodate, bichromic acid; bichromates such as sodium bichromate,potassium bichromate and the like; permanganic acid; permanganates suchas potassium permanganate, sodium permanganate and the like; lead saltssuch as lead tetraacetate and the like can be exemplified. The oxidizingagent may be used generally at least an equimolar quantity, preferablyan equimolar to 2 molar quantities per 1 mole of compound (2b) orcompound (25). Further, in case of obtaining the compound havingsulfonyl group (n is 2), the amount of oxidizing agent may be at least 2molar quantities, preferably 2 to 4 molar quantities per 1 mole ofcompound (2b) or compound (25). The said reaction is carried outgenerally at about −10 to 40° C., preferably at −10° C. to about a roomtemperature, and is finished in about 1 to 30 hours.

1-Substituted-4-nitroimidazole derivative represented by the generalformula (10) of the present invention can be prepared by the methodshown in the following Reaction scheme-9.

[wherein, R¹, R^(A) and R^(C) are the same as defined in the above].

Reaction of compound (23) with compound (11) can be carried out underthe condition similar to that employed in the reaction of compound (2)with compound (11) in the above-mentioned Reaction scheme-4.

Reaction of obtaining compound (10c) from compound (27) can be carriedout under the condition similar to that employed in the reaction ofobtaining compound (4a) from compound (16) or (17) in theabove-mentioned Reaction scheme-6.

[wherein R^(A), R¹ and n¹ are the same as defined in the above].

Reaction of obtaining compound (10d) from compound (10c) can be carriedout under the condition similar to that employed in the reaction ofobtaining compound (2c) from compound (2b) in the above-mentionedReaction scheme-8.

[wherein X¹ is the same as defined in the above].

Reaction of obtaining compound (2a) from compound (15) can be carriedout in a suitable solvent or without solvent, in the presence of anitronium haloborate, such as nitronium tetrafluoroborate as thenitrating agent.

As to the solvent, for example fatty acids or anhydride thereof, such asacetic acid, acetic anhydride and the like; inorganic acids, such asconcentrated sulfuric acid; halogenated hydrocarbons, such aschloroform, dichloromethane, carbon tetrachloride and the like;nitromethane and the like can be exemplified. Among these solvent,nitromethane is used preferably. The amount of the nitrating agent maybe at least an equimolar quantity, preferably an equimolar to 5 molarquantities per 1 mole of compound (15). The said reaction is carried outgenerally at 30° C. to about a room temperature, and is finished inabout 10 minutes to 20 hours. The said reaction is known in a method ofnitration by using the above-mentioned mixture of nitric acid-sulfuricacid. Under known nitration condition, compound (2a) can only beobtained in lower yield, and it is industrially disadvantageous.According to the present invention, by using a nitronium haloborate suchas nitronium tetrafluoroborate as nitrating agent, the objectivecompound (2a) can be obtained in high yield and high purity.

The 1-substituted-4-nitroimidazole compounds (10a) and (10b) representedby the general formula (10) of the present invention can be introducedto compounds (30a) and (30b) which are useful compounds asantitubercular agents by the following Reaction scheme-12.

[wherein R^(B) and X are the same as defined above, R² represents thefollowing group of (A), (B), (C), (D), (E), (F) or (G) indicated below;and further, R^(B) and —(CH₂)₂R² may bind to each other together withcarbon atoms adjacent thereto through nitrogen atoms, so as to form aspiro ring represented by general formula (H) indicated below.]

General formulas (A) to (H) will be explained as follows:

a group represented by the following general formula (A):—OR³  (A)

wherein R³ represents:

A1) hydrogen atom;

A2) C1-6 alkyl group;

A3) C1-6 alkoxy-C1-6 alkyl group

A4) phenyl C1-6 alkyl group (which may be substituted on the phenyl ringby at least one group selected from the group consisting of a phenylC1-6 alkoxy group, a halogen-substituted or unsubstituted C1-6 alkylgroup, a halogen-substituted or unsubstituted C1-6 alkoxy group, and aphenoxy group which may have, as a substituent, at least onehalogen-substituted or unsubstituted C1-6 alkoxy group on the phenylring);

A5) biphenylyl C1-6 alkyl group;

A6) phenyl C2-6 alkenyl group:

A7) C1-6 alkylsulfonyl group;

A8) benzenesulfonyl group which may be substituted by a C1-6 alkylgroup;

A9) C1-6 alkanoyl group;

A10) a group represented by the following general formula (Aa):

wherein R⁴ represents a C1-6 alkoxycarbonyl group; phenyl C1-6alkoxycarbonyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a phenyl C1-6alkoxy group, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group); or phenylC1-6 alkyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a phenyl C1-6alkoxy group, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

A11) biphenylyl C1-6 alkoxycarbonyl group;

A12) benzoxazolyl C1-6 alkyl group (which may be substituted on thebenzoxazole ring by at least one oxo group as a substituent);

A13) benzoxazolyl group; or

A14) oxazolyl C1-6 alkyl group (which may be substituted on the oxazolering by at least one group selected from the group consisting of aphenyl group and C1-6 alkyl group as a substituent),

a group represented by the following general formula (B):—SR⁵  (B)

wherein R⁵ represents a tetrazolyl group (which may be substituted onthe tetrazole ring by a C1-6 alkyl group or phenyl group which may havea halogen atom as a substituent), or benzoxazolyl group,

a group represented by the following general formula (C):—COOR⁶  (C)

wherein R⁶ represents a C1-6 alkyl group,

a carbamoyloxy group represented by the following general formula (D):—OOCNR⁷R⁸  (D)

wherein R⁷ and R⁸ each identically or differently represent any one of:

D1) hydrogen atom;

D2) C1-8 alkyl group;

D3) halogen-substituted C1-6 alkyl group;

D4) C1-6 alkoxycarbonyl-C1-6 alkyl group;

D5) C3-8 cycloalkyl group;

D6) phenyl C1-6 alkyl group (which may be substituted on the phenyl ringby at least one group selected from the group consisting of a halogenatom, a halogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

D7) phenyl group (which may be substituted on the phenyl ring by 1 to 3groups selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, ahalogen-substituted or unsubstituted C1-6 alkoxy group, a C1-6 alkanoylgroup, a carboxyl group, a C1-6 alkoxycarbonyl group, a phenyl C1-6alkoxycarbonyl group, a carbamoyl group, a C1-6 alkylcarbamoyl group, anaminosulfonyl group, and a morpholino group);

D8) naphthyl group;

D9) pyridyl group; and

D10) R⁷ and R⁸ may bind to each other together with nitrogen atomsadjacent thereto directly or through other hetero atoms or carbon atoms,so as to form a saturated heterocyclic group shown in any one of (D10-1)to (D10-3) indicated below, or benzene condensed heterocyclic groupshown in any one of (D10-4) to (D10-7) indicated below:

(D10-1) piperazinyl group represented by the following general formula(Da):

wherein R⁹ represents:

(Da1) hydrogen atom;

(Da2) C1-6 alkyl group;

(Da3) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Da4) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Da5) C1-6 alkoxycarbonyl group;

(Da6) phenyl C1-6 alkoxycarbonyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl groupand a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Da7) phenyl C3-6 alkenyloxycarbonyl group (which may have at least onehalogen-substituted or unsubstituted C1-6 alkyl group on the phenylring); or

(Da8) phenyl C1-6 alkylidene substituted amino group (which may besubstituted on the phenyl ring by at least one halogen-substituted orunsubstituted C1-6 alkyl group as a substituent),

(D10-2) a group represented by the following general formula (Db):

wherein the dotted line represents that the bond may be a double bond,and R¹⁰ represents:

(Db1) hydrogen atom;

(Db2) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Db3) phenoxy group (which may be substituted on the phenyl ring by atleast one halogen-substituted or unsubstituted C1-6 alkyl group); or

(Db4) phenylamino group (which may be substituted on the phenyl ring byat least one halogen-substituted or unsubstituted C1-6 alkyl group),

(D10-3) morpholino group;

(D10-4) indolinyl group (which may be substituted on the indoline ringby at least one halogen atom as a substituent);

(D10-5) isoindolinyl group (which may be substituted on the isoindolinering by at least one halogen atom as a substituent);

(D10-6) 1,2,3,4-tetrahydroquinolyl group, (which may be substituted onthe 1,2,3,4-tetrahydro-quinoline ring by at least one halogen atom as asubstituent); or

(D10-7) 1,2,3,4-tetrahydroisoquinolyl group, (which may be substitutedon the 1,2,3,4-tetrahydroisoquinoline ring by at least one halogen atomas a substituent),

a phenoxy group represented by the following general formula (E):

wherein X represents a halogen atom or amino substituted C1-6 alkylgroup which may have a C1-6 alkyl group as a substituent, m representsan integer of 0 to 3, and R¹¹ represents:

E1) hydrogen atom;

E2) halogen-substituted or unsubstituted C1-6 alkyl group;

E3) halogen-substituted or unsubstituted C1-6 alkoxy group;

E4) a group represented by the following general formula (Ea):—(W)o-NR¹²R¹³  (Ea)

wherein W represents a group —CO— or a C1-6 alkylene group, o representsan integer of 0 or 1, and R¹² and R¹³ each identically or differentlyrepresent any one of:

(Ea1) hydrogen atom;

(Ea2) C1-6 alkyl group;

(Ea3) C1-6 alkanoyl group;

(Ea4) C1-6 alkoxycarbonyl group;

(Ea5) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group, ahalogen-substituted or unsubstituted C1-6 alkoxy group, and a phenoxygroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group as asubstituent), and the alkyl portion may be substituted by a C1-6alkoxyimino group);

(Ea6) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Ea7) benzoyl group (which may be substituted on the phenyl ring by atleast one group selected from a group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Ea8) pyridyl group (which may be substituted on the pyridine ring by atleast one halogen atom as a substituent);

(Ea9) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Ea10) phenoxy C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group); and

(Ea11) benzoyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group),

E5) imidazolyl;

E6) triazolyl;

E7) morpholino group;

E8) thiomorpholino group;

E9) s-oxide thiomorpholino group;

E10) piperidyl group represented by the following general formula (Eaa):

wherein W and o are the same as above, R^(14A) represents a hydrogenatom, hydroxyl group, C1-6 alkoxy group, or phenyl group (which may besubstituted by halogen on the phenyl ring); the dotted line representsthat the bond may be a double bond, and when the dotted line representsa double bond, it means that only R¹⁴ is substituted; R¹⁴ and R^(14A)may bind to each other together with carbon atoms adjacent thereto toform a C1-4 alkylenedioxy group, and R¹⁴ represents:

(Eaa1) hydrogen atom;

(Eaa2) C1-6 alkoxycarbonyl group;

(Eaa3) phenoxy group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom; ahalogen-substituted or unsubstituted C1-6 alkyl group; ahalogen-substituted or unsubstituted C1-6 alkoxy group; a C1-4alkylenedioxy group; a C1-6 alkoxycarbonyl group; a cyano group; a C2-6alkenyl group; a nitro group; a phenyl group; an amino group which mayhave, as a substituent, a group selected from the group consisting of aphenyl group, a C1-6 alkyl group, a carbamoyl group and a C1-6 alkanoylgroup; a C1-6 alkanoyl-substituted C1-6 alkyl group; a hydroxyl group; aC1-6 alkoxycarbonyl-substituted C1-6 alkyl group; a phenyl C1-6 alkylgroup; a C1-6 alkanoyl group; a C1-6 alkylthio group; a 1,2,4-triazolylgroup; an isoxazolyl group; an imidazolyl group; a benzothiazolyl group;a 2H-benzotriazolyl group; a pyrrolyl group; a benzoxazolyl group; apiperazinyl group (which may be substituted on the piperazine ring by atleast one group selected from the group consisting of a C1-6alkoxycarbonyl group and a phenyl C1-6 alkyl group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group) as a substituent); a piperidinyl group(which may be substituted on the piperidine ring by at least one groupselected from the group consisting of an amino group (which may besubstituted on the amino group by at least one group selected from thegroup consisting of a C1-6 alkyl group and a phenyl group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group) as a substituent)); and a carbamoylgroup);

(Eaa4) hydroxyl group;

(Eaa5) carboxy group;

(Eaa6) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a phenoxy group(which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group as asubstituent), a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup as a substituent);

(Eaa7) C1-6 alkoxy group;

(Eaa8) C3-8 cycloalkyl-C1-6 alkoxy group;

(Eaa9) phenylcarbamoyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Eaa10) tetrahydropyranyloxy group;

(Eaa11) 1,3-dioxolanyl group;

(Eaa12) oxo group;

(Eaa13) naphthyloxy group (which may be substituted on the naphthalenering by at least one C1-6 alkyl group as a substituent);

(Eaa14) 2,3-dihydrobenzofuryloxy group (which may be substituted on the2,3-dihydrobenzofuran ring by at least one group selected from the groupconsisting of a C1-6 alkyl group and an oxo group);

(Eaa15) benzothiazolyloxy group (which may be substituted on thebenzothiazole ring by at least one C1-6 alkyl group);

(Eaa16) 1,2,3,4-tetrahydronaphthyloxy group (which may be substituted onthe 1,2,3,4-tetrahydronaphthalene ring by at least one oxo group as asubstituent);

(Eaa17) 1,3-benzoxathiolanyloxy group (which may be substituted on the1,3-benzoxathiolan ring by at least one oxo group as a substituent);

(Eaa18) isoquinolyloxy group;

(Eaa19) pyridyloxy group;

(Eaa20) quinolyloxy group (which may be substituted on the quinolinering by at least one C1-6 alkyl group as a substituent);

(Eaa21) dibenzofuryloxy group;

(Eaa22) 2H-chromenyloxy group (which may be substituted on the2H-chromen ring by at least one oxo group as a substituent);

(Eaa23) benzisoxazolyloxy group;

(Eaa24) quinoxalyloxy group;

(Eaa25) 2,3-dihydro-1H-indenyloxy group (which may be substituted on the2,3-dihydro-1H-indene ring by at least one oxo group as a substituent);

(Eaa26) benzofurazanyloxy group; or

(Eaa27) phenyl C2-6 alkenyl group (which may be substituted on thephenyl ring by at least one group selected from a group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group),

E11) a group represented by the following general formula (Eab):

wherein o is the same as above, W₁ represents a C1-6 alkylene group andR¹⁵ represents:

(Eab1) hydrogen atom;

(Eab2) C1-6 alkyl group (wherein the alkyl group may be substituted by amorpholino group, benzoyl group, carbamoyl group which may have a C1-6alkyl group as a substituent, or cyano group);

(Eab3) C3-8 cycloalkyl group;

(Eab4) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a cyano group, a phenyl group, a nitro group, a C1-6alkylthio group, a C1-6 alkylsulfonyl group, a phenyl C1-6 alkoxy group,a C2-6 alkanoyloxy group, a halogen-substituted or unsubstituted C1-6alkyl group, a halogen-substituted or unsubstituted C1-6 alkoxy group,and a 1,2,3-thiadiazolyl group);

(Eab5) C2-6 alkenyl group;

(Eab6) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, acyano group, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Eab7) C1-6 alkanoyl group;

(Eab8) phenyl C2-6 alkanoyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Eab9) benzoyl group (which may be substituted on the benzene ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Eab10) C1-20 alkoxycarbonyl group (which may be substituted on thealkoxy group by at least one group selected from the group consisting ofa halogen atom, an amino group which may have a C1-6 alkyl group as asubstituent, and a C1-6 alkoxy-substituted C1-6 alkoxy group);

(Eab11) phenyl C1-6 alkoxycarbonyl group (which may be substituted onthe phenyl ring by at least one group selected from the group consistingof a halogen atom, a halogen-substituted or unsubstituted C1-6 alkylgroup, a halogen-substituted or unsubstituted C1-6 alkoxy group, a nitrogroup, a halogen-substituted or unsubstituted C1-6 alkylthio group, anamino group which may have a C1-6 alkanoyl group, a phenyl C1-6 alkoxygroup, a C1-6 alkoxycarbonyl group, and a 1,2,3-thiadiazolyl group);

(Eab12) a phenyl C3-6 alkenyloxycarbonyl group (which may be substitutedon the phenyl ring by at least one group selected from the groupconsisting of a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup);

(Eab13) phenoxycarbonyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Eab14) phenyl C1-6 alkylcarbamoyl group (which may be substituted onthe phenyl ring by at least one group selected from the group consistingof a halogen atom, a halogen-substituted or unsubstituted C1-6 alkylgroup, and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Eab15) phenylcarbamoyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Eab16) benzofuryl-substituted C1-6 alkoxycarbonyl group which may besubstituted by at least one halogen atom on the benzofuran ring;

(Eab17) benzothienyl C1-6 alkoxycarbonyl group (which may be substitutedon the benzothiophene ring by at least one group selected from the groupconsisting of a halogen atom and a halogen-substituted or unsubstitutedC1-6 alkoxy group as a substituent);

(Eab18) naphthyl-substituted C1-6 alkoxycarbonyl group;

(Eab19) pyridyl-substituted C1-6 alkoxycarbonyl group (which may besubstituted on the pyridine ring by at least one halogen atom as asubstituent);

(Eab20) furyl-substituted C1-6 alkoxycarbonyl group (which may besubstituted on the furan ring by at least one nitro group as asubstituent);

(Eab21) thienyl-substituted C1-6 alkoxycarbonyl group (which may have atleast one halogen atom as a substituent on the thiophene ring);

(Eab22) thiazolyl-substituted C1-6 alkoxycarbonyl group (which may besubstituted on the thiazole ring by at least one group selected from thegroup consisting of a C1-6 alkyl group and a phenyl group (which may besubstituted on the phenyl ring by at least one halogen-substituted orunsubstituted C1-6 alkyl group));

(Eab2.3) tetrazolyl-substituted C1-6 alkoxycarbonyl group (which may besubstituted on the tetrazole ring by at least one group selected fromthe group consisting of a C1-6 alkyl group and a phenyl group (which mayhave at least one halogen atom as a substituent on the phenyl ring) as asubstituent);

(Eab24) 2,3-dihydro-1H-indenyloxycarbonyl group;

(Eab25) adamantane-substituted C1-6 alkoxycarbonyl group;

(Eab26) phenyl C3-6 alkynyloxycarbonyl group;

(Eab27) phenylthio C1-6 alkoxycarbonyl group;

(Eab28) phenyl C1-6 alkoxy-substituted C1-6 alkoxycarbonyl group;

(Eab29) C2-6 alkenyloxycarbonyl group;

(Eab30) C2-6 alkynyloxycarbonyl group;

(Eab31) C3-8 cycloalkyl-substituted C1-6 alkoxycarbonyl group; or

(Eab32) benzoyl-substituted C1-6 alkoxycarbonyl group,

E12) a group represented by the following general formula (Eb):

wherein the dotted line represents that the bond may be a double bond,and R¹⁴ is defined as the same as R¹⁵;

E13) a group represented by the following general formula (Ec):

wherein R¹⁷ represents:

(Ec1) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Ec2) C1-6 alkoxycarbonyl group; or

(Ec3) phenyl C1-6 alkoxycarbonyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group),

E14) pyridyl group;

E15) a group represented by the following general formula (Ee):

wherein R⁴⁶ represents a phenyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group as asubstituent); phenyl C1-6 alkyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group); phenylC1-6 alkoxycarbonyl group (which may be substituted on the phenyl ringby at least one group selected from the group consisting of a halogenatom, a halogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); or C1-6alkoxycarbonyl group,

E16) phenoxy group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

E17) benzoyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

E18) 8-azabicyclo[3,2,1]octyl group (which may be substituted on the8-azabicyclo[3,2,1]octane ring by at least one phenoxy group (which maybe substituted on the phenyl ring by at least one group selected fromthe group consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group) as a substituent);

E19) a group represented by the following general formula (Ef):—CH═N—NR⁴⁷R⁴⁸  (Ef)

wherein R⁴⁷ and R⁴⁸ each identically or differently represent any one ofa hydrogen atom, a C1-6 alkyl group, a phenyl group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group), or a pyridyl group (which may besubstituted on the pyridine ring by at least one halogen-substituted orunsubstituted C1-6 alkyl group as a substituent); and further, R⁴⁷ andR⁴⁸ may bind to each other together with nitrogen atoms adjacent theretodirectly or through other hetero atoms, so as to form a 5-7 memberedsaturated heterocyclic ring, which may be substituted on theheterocyclic ring by at least one phenyl group (which may be substitutedon the phenyl ring by at least one group selected from the groupconsisting of a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup) as a substituent;

E20) phenyl C1-6 alkoxy group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

E21) amino substituted C2-6 alkenyl group (which may be substituted onthe amino group by at least one group selected from the group consistingof a C1-6 alkyl group and a phenyl group (which may be substituted onthe phenyl ring by at least one group selected from the group consistingof a halogen atom, a halogen-substituted or unsubstituted C1-6 alkylgroup, and a halogen-substituted or unsubstituted C1-6 alkoxy group));or

E22) oxazolidinyl group (which may be substituted on the oxazolidinering by at least one oxo group as a substituent),

a group represented by the following general formula (F):—NR¹⁹R²⁰  (F)

wherein R¹⁹ and R²⁰ each identically or differently represent any oneof:

F1) hydrogen atom;

F2) C1-6 alkyl group;

F3) phenyl C1-6 alkyl group (which may be substituted on the phenyl ringby at least one group selected from the group consisting of: a phenoxygroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); a halogen atom;a halogen-substituted or unsubstituted C1-6 alkyl group; ahalogen-substituted or unsubstituted C1-6 alkoxy group; an amino groupwhich may have at least one group selected from the group consisting ofa C1-6 alkyl group, and a phenyl C1-6 alkyl group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); a piperazinyl group (which may besubstituted on the piperazine ring by at least one phenyl C1-6 alkylgroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group) as asubstituent); and a piperidyl group (which may be substituted on thepiperidine ring by at least one amino group which may have a groupselected from the group consisting of a phenyl group (which may besubstituted on the phenyl ring by at least one group selected from agroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group) and a C1-6 alkyl group as asubstituent));

F4) phenoxy C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted, C1-6 alkoxy group);

F5) amino C1-6 alkyl group (which may be substituted on the amino groupby at least one group selected from the group consisting of a C1-6 alkylgroup, a C1-6 alkoxycarbonyl group, and a phenyl group which may besubstituted on the phenyl group by at least one group selected from agroup consisting of a halogen atom and a halogen-substituted orunsubstituted C1-6 alkyl group);

F6) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, aphenoxy group (which may be substituted on the phenyl ring by at leastone group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group), and a C1-6alkoxycarbonyl group);

F7) C1-6 alkoxycarbonyl group;

F8) phenyl C1-6 alkoxycarbonyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

F9) a group represented by the following general formula (Fa):

wherein R²¹ represents a C1-6 alkoxycarbonyl group; phenyl C1-6alkoxycarbonyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, acyano group, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group); phenylC1-6 alkyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom anda halogen-substituted or unsubstituted C1-6 alkyl group); or phenylgroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, a cyano group, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

F10) 1-substituted-4-piperidyl group represented by the followingformula (Fb):

wherein R²² represents a C1-6 alkoxycarbonyl group; phenyl C1-6alkoxycarbonyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); or phenyl group(which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, a cyano group, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

F11) piperidyl C1-6 alkyl group (which may have at least one phenoxygroup (which may have at least one halogen-substituted or unsubstitutedC1-6 alkyl group as a substituent) as a substituent);

F12) in addition, R¹⁹ and R²⁰ may bind to each other together withnitrogen atoms adjacent thereto directly or through other hetero atomsor carbon atoms, so as to form a heterocyclic ring shown in any one of(F12-1) to (F12-10) indicated below:

(F12-1) a group represented by the following formula (Fc):

wherein the dotted line represents that the bond may be a double bond,and R²³ represents:

(Fc1) C1-6 alkyl group;

(Fc2) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc3) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of: a halogen atom; ahalogen-substituted or unsubstituted C1-6 alkyl group; ahalogen-substituted or unsubstituted C1-6 alkoxy group; an amino groupwhich may have, as a substituent, a group selected from the groupconsisting of a C1-6 alkyl group and a phenyl C1-6 alkyl group (whichmay be substituted on the phenyl ring by at least one group selectedfrom the group consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); a phenoxy group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); a phenyl C1-6 alkoxy group (which maybe substituted on the phenyl ring by at least one group selected fromthe group consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); and a piperidyl group (which may have,on the piperidine ring, as a substituent, at least one amino group thatmay have a group selected from the group consisting of a phenyl C1-6alkyl group (which may be substituted on the phenyl ring by at least onegroup selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group) and a C1-6 alkylgroup));

(Fc4) phenyl C1-6 alkoxy group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc5) biphenylyl C1-6 alkoxy group;

(Fc6) phenyl C3-6 alkenyloxy group which may be substituted on thephenyl ring by at least one halogen atom;

(Fc7) phenoxy group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, acyano group, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc8) benzoyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc9) C1-6 alkoxycarbonyl group;

(Fc10) phenyl C1-6 alkoxycarbonyl group (which may be substituted on thephenyl ring by at least one halogen-substituted or unsubstituted C1-6alkoxy group);

(Fc11) phenyl C1-6 alkylcarbamoyl group wherein at least one halogen maybe substituted on the phenyl ring;

(Fc12) phenylcarbamoyl group (which may be substituted on the phenylring by at least one group selected from a group consisting of a halogenatom, a halogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc13) phenylthio group (which may be substituted on the phenyl ring byat least one halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc14) phenyl sulfoxide (which may be substituted on the phenyl ring byat least one halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fc15) pyridyl C1-6 alkoxy group; or

(Fc16) a group represented by the following general formula (Fca):—(C═O)o-NR²⁴R²⁵  (Fca)

wherein o is the same as above, and each of R²⁴ and R²⁵ represents:

(Fca1) hydrogen atom;

(Fca2) C1-6 alkyl group;

(Fca3) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fca4) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, acyano group, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fca5) C1-6 alkanoyl group;

(Fca6) phenyl C2-6 alkanoyl group that may be substituted on the phenylring by at least one halogen atom;

(Fca7) benzoyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Fca8) C1-6 alkoxycarbonyl group;

(Fca9) phenyl C1-6 alkoxycarbonyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fca10) phenylcarbamoyl group (which may be substituted on the phenylring by at least one halogen-substituted or unsubstituted C1-6 alkylgroup);

(Fca11) piperidyloxycarbonyl group (which may be substituted on thepiperidine ring by at least one phenyl group (which may be substitutedon the phenyl ring by at least one halogen-substituted or unsubstitutedC1-6 alkyl group) as a substituent); or

(Fca12) R²⁴ and R²⁵ may form a 5-6 membered saturated heterocyclic ringthrough nitrogen atoms adjacent thereto, which may be substituted on theheterocyclic ring by at least one group selected from the groupconsisting of a C1-6 alkoxycarbonyl group; a benzoyl group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); a phenoxy group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); a phenyl C1-6 alkyl group (which maybe substituted on the phenyl ring by at least one group selected fromthe group consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); a phenyl C1-6 alkoxycarbonyl group(which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); a phenyl C2-6alkenyl group (which may be substituted on the phenyl ring by at leastone group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); and a phenylgroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group),

(F12-2) 4-substituted-1-piperazinyl group represented by the followinggeneral formula (Fd):

wherein R²⁶ represents:

(Fd1) hydrogen atom;

(Fd2) C1-6 alkyl group;

(Fd3) C3-8 cycloalkyl group;

(Fd4) C3-8 cycloalkyl C1-6 alkyl group;

(Fd5) C1-6 alkoxycarbonyl C1-6 alkyl group;

(Fd6) phenyl C2-6 alkenyl group;

(Fd7) phenyl C1-6 alkyl group (which may be substituted on the phenylring by 1 to 3 groups selected from the group consisting of: a halogenatom; a cyano group; a halogen-substituted or unsubstituted C1-6 alkylgroup; C3-8 cycloalkyl group; a halogen-substituted or unsubstitutedC1-6 alkoxy group; an amino group which may have a C1-6 alkyl group as asubstituent; a C1-6 alkoxycarbonyl group; a phenoxy group; a phenyl C1-6alkyl group; a phenyl C2-6 alkenyl group; a pyridyl group; an imidazolylgroup; and a piperidyl group);

(Fd8) biphenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group, ahalogen-substituted or unsubstituted C1-6 alkoxy group, and an aminogroup which may have a C1-6 alkyl group as a substituent);

(Fd9) naphthyl C1-6 alkyl group;

(Fd10) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of: a halogen atom; acyano group; an amino group which may have a C1-6 alkyl group as asubstituent; a halogen-substituted or unsubstituted C1-6 alkyl group; ahalogen-substituted or unsubstituted C1-6 alkoxy group; a C1-6alkoxycarbonyl group; a carboxyl group; a phenoxy group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); an amino C1-6 alkyl group (which mayhave on the amino group at least one group selected from the groupconsisting of a phenyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group) and a C1-6alkyl group); and a phenyl C1-6 alkoxy group (which may be substitutedon the phenyl ring by at least one group selected from the groupconsisting of a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup));

(Fd11) biphenyl group (which may be substituted on the phenyl ring by atleast one halogen-substituted or unsubstituted C1-6 alkyl groups);

(Fd12) amino group, amino group which is substituted by a C1-6alkoxycarbonyl group, phenyl C1-6 alkylamino group (which may besubstituted on the phenyl ring by at least one halogen-substituted orunsubstituted C1-6 alkyl group), or phenylamino group (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen-substituted or unsubstituted C1-6 alkylgroup and a halogen atom);

(Fd13) benzoyl C1-6 alkyl group (which may have on the phenyl ring atleast one halogen atom as a substituent);

(Fd14) phenylcarbamoyl C1-6 alkyl group (which may be substituted on thephenyl ring by at least one halogen-substituted or unsubstituted C1-6alkyl group);

(Fd15) thiazolyl C1-6 alkyl group (which may be substituted on thethiazole ring by at least one group selected from the group consistingof a halogen-substituted or unsubstituted phenyl group and a C1-6 alkylgroup);

(Fd16) oxazolyl C1-6 alkyl group (which may be substituted on theoxazole ring by at least one group selected from the group consisting ofa halogen-substituted or unsubstituted phenyl group and a C1-6 alkylgroup);

(Fd17) indolyl C1-6 alkyl group;

(Fd18) furyl C1-6 alkyl group (which may be substituted on the furanring by at least one halogen-substituted or unsubstituted phenyl group);

(Fd19) imidazolyl C1-6 alkyl group (which may be substituted on theimidazole ring by a phenyl group);

(Fd20) quinolyl C1-6 alkyl group;

(Fd21) tetrazolyl group (which may be substituted on the tetrazole ringby a phenyl group);

(Fd22) pyrimidyl group which may be substituted by a phenyl group;

(Fd23) pyridyl group;

(Fd24) benzoxazolyl group;

(Fd25) benzothiazolyl group;

(Fd26) benzoxazolyl C1-6 alkyl group (which may have on the benzoxazolering at least one oxo group as a substituent);

(Fd27) phenoxy C2-6 alkanoyl group which may be substituted on thephenyl ring by a halogen atom;

(Fd28) phenylthio C2-6 alkanoyl group which may be substituted on thephenyl ring by a halogen atom;

(Fd29) phenyl C2-6 alkanoyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fd30) benzoyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, ahalogen-substituted or unsubstituted C1-6 alkoxy group, and an aminogroup which may have a C1-6 alkyl group as a substituent);

(Fd31) biphenylylcarbonyl group;

(Fd32) pyridylcarbonyl group;

(Fd33) phenyl C2-6 alkenylcarbonyl group wherein a halogen atom may besubstituted on the phenyl ring;

(Fd34) phenyl C1-6 alkylsulfonyl group wherein a halogen atom may besubstituted on the phenyl ring;

(Fd35) benzenesulfonyl group (which may be substituted on the benzenering by at least one group selected from the group consisting of ahalogen atom and a C1-6 alkyl group);

(Fd36) a group represented by the following general formula (Fda):—COOR²⁷  (Fda)

wherein R²⁷ represents:

(Fda1) halogen-substituted or unsubstituted C1-8 alkyl group;

(Fda2) C3-8 cycloalkyl group;

(Fda3) C3-8 cycloalkyl-C1-6 alkyl group;

(Fda4) C1-6 alkoxy-C1-6 alkyl group;

(Fda5) amino-C1-6 alkyl group which may have a C1-6 alkyl group;

(Fda6) a group represented by the following general formula (Fdb):

wherein R²⁶, R²⁹, and R³⁰ represent a hydrogen atom, a C1-6 alkyl group,or a phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group), respectively;

(Fda7) phenyl C1-6 alkyl group (which may be substituted on the phenylring by 1 to 5 groups selected from the group consisting of: a halogenatom; a halogen-substituted or unsubstituted C1-6 alkyl group; ahalogen-substituted or unsubstituted C1-6 alkoxy group; ahalogen-substituted or unsubstituted C1-6 alkylthio group; a phenyl C1-6alkoxy group; a hydroxy group; a C1-6 alkylsulfinyl group; a C1-6alkylsulfonyl group; C1-6 alkylsulfonyloxy group; a cyano group; a C1-6alkanoyl group; a benzoyl group; a phenyl C1-6 alkyl group which mayhave a C1-6 alkoxy group in the alkyl portion; an amino group; a nitrogroup; a carbamoyl group; a C1-6 alkanoylamino group; a C1-6alkoxycarbonyl group; a C1-6 alkylaminocarbonyl group; a C1-6alkoxycarbonylamino group; a tri-C1-6-alkylsiloxy group; a pyrrolylgroup; a tetrahydropyranyloxy group; and an imidazolyl group);

(Fda8) biphenylyl C1-6 alkyl group;

(Fda9) benzhydryl group (which may be substituted on the benzene ring byat least one group selected from the group consisting of a halogen atom,a trifluoromethyl group, and a trifluoromethoxy group);

(Fda10) phenoxy C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fda11) phenyl C2-6 alkynyl group (which may be substituted on thephenyl ring by at least one halogen-substituted or unsubstituted C1-6alkyl group as a substituent);

(Fda12) pyridyl C1-6 alkyl group;

(Fda13) a group represented by the following general formula (Fdc):

wherein R³¹ represents a phenyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a cyano group, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup); phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group); orbenzoyl group (which may be substituted on the phenyl ring by at leastone group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group),

(Fda14) piperidino C1-6 alkyl group (which may be substituted on thepiperidine ring by a phenoxy group which may have at least onehalogen-substituted or unsubstituted alkyl group as a substituent on thephenyl ring);

(Fda15) amino C1-6 alkyl group which may have, as a substituent, atleast one group selected from the group consisting of a C1-6 alkyl groupand a phenyl group which may have, as a substituent, ahalogen-substituted or unsubstituted C1-6 alkoxy group on the phenylring;

(Fda16) 1,2,3,6-tetrahydropyridyl C1-6 alkyl group (which may besubstituted on the 1,2,3,6-tetrahydropyridine ring by at least onephenyl group which may have, as a substituent, at least onehalogen-substituted or unsubstituted C1-6 alkoxy group on the phenylring);

(Fda17) naphthyl C1-6 alkyl group;

(Fda18) fluorenyl C1-6 alkyl group;

(Fda19) pyridyl C1-6 alkyl group;

(Fda20) furyl C1-6 alkyl group (which may be substituted on the furanring by a halogen-substituted or unsubstituted phenyl group);

(Fda21) thienyl C1-6 alkyl group;

(Fda22) oxazolyl C1-6 alkyl group (which may be substituted on theoxazole ring by a halogen atom or a halogen-substituted or unsubstitutedphenyl group);

(Fda23) oxadiazolyl C1-6 alkyl group (which may be substituted on theoxadiazole ring by a halogen-substituted or unsubstituted phenyl group);

(Fda24) pyrazolyl C1-6 alkyl group (which may be substituted on thepyrazole ring by a halogen-substituted or unsubstituted phenyl group);

(Fda25) benzothienyl C1-6 alkyl group (which may be substituted on thebenzothiophene ring by at least one group selected from the groupconsisting of a halogen atom and a halogen-substituted or unsubstitutedC1-6 alkoxy group);

(Fda26) thienyl C1-6 alkyl group that may be substituted on thethiophene ring by a halogen atom;

(Fda27) benzothiazolyl C1-6 alkyl group;

(Fda28) benzofuryl C1-6 alkyl group which may be substituted on thebenzofuran ring by a halogen atom;

(Fda29) indolinyl C1-6 alkyl group (which may be substituted on theindoline ring by at least one group selected from the group consistingof a C1-6 alkyl group and an oxo group);

(Fda30) benzoxazolyl C1-6 alkyl group (which may be substituted on thebenzoxazole ring by at least one group selected from a group consistingof a halogen atom, a C1-6 alkyl group, and an oxo group);

(Fda31) chromenyl C1-6 alkyl group;

(Fda32) 1,2,3,4-tetrahydroquinolyl C1-6 alkyl group (which may besubstituted on the quinoline ring by at least one group selected fromthe group consisting of a C1-6 alkyl group and an oxo group);

(Fda33) thiazolyl C1-6 alkyl group (which may be substituted on thethiazole ring by at least one group selected from the group consistingof a halogen atom, a halogen-substituted or unsubstituted phenyl group,and a C1-6 alkyl group); or

(Fda34) tetrazolyl C1-6 alkyl group (which may be substituted on thetetrazole ring by a group selected from the group consisting of ahalogen-substituted or unsubstituted phenyl group and a C1-6 alkylgroup);

(Fd37) a group represented by the following general formula (Fe):—Z—NR³²R³³  (Fe)

wherein Z represents —C═O or —C═S, and R³² and R³³ each identically ordifferently represent any one of:

(Fe1) hydrogen atom;

(Fe2) C1-6 alkyl group;

(Fe3) C3-8 cycloalkyl group;

(Fe4) phenyl C1-6 alkyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fe5) phenyl C2-6 alkenyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Fe6) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); or

(Fe7) R³² and R³³ may bind to each other together with nitrogen atomsadjacent thereto through other carbon atoms, so as to form a piperidinering or 1,2,3,6-tetrahydropyridine ring, which may be substituted on thepiperidine or 1,2,3,6-tetrahydropyridine ring by a phenyl group, whichmay be substituted at least one group selected from the group consistingof a halogen atom and a halogen-substituted or unsubstituted C1-6 alkylgroup,

(Fd38) a group represented by the following general formula (Ff):

wherein R³⁴ represents a hydrogen atom or C1-6 lower alkyl group, andR³⁵ represents:

(Ff1) C3-8 cycloalkyl group;

(Ff2) C3-8 cycloalkenyl group;

(Ff3) a group represented by the following general formula (Ffa):

wherein each of R³⁶, R³⁷, and R³⁸ represents: a hydrogen atom; C1-6alkyl group; phenyl group (which may be substituted on the phenyl ringby at least one 1 to 5 groups selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group, ahalogen-substituted or unsubstituted C1-6 alkoxy group, a C1-4alkylenedioxy group, a C1-6 alkylsulfonyl group, a halogen-substitutedor unsubstituted C1-6 alkylthio group, a nitro group, and an amino groupwhich may have a C1-6 alkanoyl group as a substituent); benzofuryl group(which may be substituted on the benzofuran ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); biphenylylgroup; furyl group (which may be substituted on the furan ring by aphenyl group which may have a halogen atom as a substituent); orthiazolyl group (which may be substituted on the thiazole ring by atleast one phenyl group which may have a halogen atom as a substituent),

(Ff4) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of: a halogen atom; ahalogen-substituted or unsubstituted C1-6 alkyl group; a C3-8 cycloalkylgroup; a hydroxyl group; a halogen-substituted or unsubstituted C1-8alkoxy group; a C3-8 cycloalkoxy group; a C1-4 alkylenedioxy group; acyano group; a nitro group; a phenyl C2-6 alkenyl group; a C2-6alkanoyloxy group; an amino group which may have a C1-6 alkanoyl groupas a substituent; a C1-6 alkylsulfonylamino group; a phenyl C1-6 alkoxygroup; a phenoxy group; an amino group which has at least one C1-6 alkylgroup as a substituent; an amino group which has at least one phenylgroup as a substituent; an amino C1-6 alkoxy group which may have atleast one C1-6 alkyl group as a substituent; a C1-6 alkoxycarbonylgroup; a C1-6 alkoxycarbonyl C1-6 alkoxy group; a C1-6 alkylthio group;a pyrrolyl group; an imidazolyl group; a piperidyl group; a morpholinogroup; a pyrrolidinyl group; a thienyl group; a benzofuryl group; apiperazinyl group (which may be substituted on the piperazine ring by atleast one group selected from the group consisting of a C1-6 alkylgroup, a phenyl C1-6 alkyl group, and a benzoyl group which may have atleast one C1-6 alkyl group as a substituent); a quinolyl group that maybe substituted on the quinoline ring by at least one group selected fromthe group consisting of a C1-6 alkoxy group and an oxo group; apiperidylcarbonyl group which may be substituted on the piperidine ringby a carbostyril group; and a triazolyl group);

(Ff5) naphthyl group which may be substituted on the naphthalene ring byat least one group selected from the group consisting of a halogen atom,a halogen-substituted or unsubstituted C1-6 alkoxy group, and an aminogroup which may have a C1-6 alkyl group as a substituent;

(Ff6) biphenylyl group (which may be substituted on the biphenylyl ringby at least one group selected from the group consisting of a halogenatom, a halogen-substituted or unsubstituted C1-9 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Ff7) fluorenyl group; pyrenyl group;

(Ff8) benzofuryl group (which may be substituted on the benzofuran ringby at least one group selected from the group consisting of a halogenatom, a halogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group);

(Ff9) benzothienyl group (which may be substituted on the benzothiophenering by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group);

(Ff10) pyridyl group (which may be substituted on the pyridine ring byat least one group selected from the group consisting of a halogen atom,a halogen-substituted or unsubstituted C1-6 alkyl group, a phenyl group(which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group), a furyl group,and a thienyl group);

(Ff11) furyl group (which may be substituted on the furan ring by 1 to 3groups selected from the group consisting of a C1-6 alkyl group, a nitrogroup, and a phenyl group (which may be substituted on the phenyl ringby at least one group selected from the group consisting of a halogenatom, a halogen-substituted or unsubstituted C1-6 alkyl group, ahalogen-substituted or unsubstituted C1-6 alkoxy group, and a nitrogroup));

(Ff12) benzothiazole group (which may have, on the benzothiazole ring,at least one phenyl group that may have, as a substituent, a C1-6 alkoxygroup on the phenyl ring);

(Ff13) thienyl group (which may have, on the thiophene ring, at leastone group selected from the group consisting of a halogen atom, a nitrogroup, a C1-6 alkyl group, a pyrazolyl group which may be substituted onthe pyrazole ring by at least one halogen-substituted or unsubstitutedC1-6 alkyl group as a substituent, and a thienyl group which may have ahalogen atom on the thiophene ring);

(Ff14) indolyl group (which may be substituted on the indole ring by atleast one group selected from the group consisting of a phenylsulfonylgroup which may have a C1-6 alkyl group as a substituent, a phenyl C1-6alkyl group, a C1-6 alkoxycarbonyl group, and a phenyl group);

(Ff15) pyrrolyl group (which may be substituted on the pyrrole ring byat least one group selected from the group consisting of a phenyl groupwhich may be substituted by at least one halogen-substituted orunsubstituted C1-6 alkyl group, and a C1-6 alkyl group);

(Ff16) coumaryl group;

(Ff17) benzimidazolyl group (which may be substituted on thebenzimidazole ring by at least one thienyl group as a substituent);

(Ff18) oxazolyl group (which may be substituted on the oxazole ring byat least one phenyl group that may have a halogen atom as asubstituent);

(Ff19) thiazolyl group (which may be substituted on the thiazole ring byat least one phenyl group, wherein at least one group selected from thegroup consisting of a halogen atom, a nitro group, and a phenyl group);

(Ff20) quinolyl group;

(Ff21) 3,4-dihydrocarbostyril group (which may be substituted on the3,4-dihydrocarbostyril ring by at least one group selected from thegroup consisting of a C1-6 alkoxy group, a C1-6 alkyl group, and aphenyl C1-6 alkoxy group), or carbostyril group (which may besubstituted on the carbostyril ring by at least one group selected fromthe group consisting of a C1-6 alkoxy group, a C1-6 alkyl group, and aphenyl C1-6 alkoxy group);

(Ff22) imidazo[2,1-b]thiazolyl group;

(Ff23) imidazo[2,1-a]pyridyl group;

(Ff24) chromanyl group (which may be substituted on the chroman ring byat least one C1-6 alkyl group); or

(Ff25) 2,3-dihydrobenzofuryl group, or

(Fd39) a group represented by the following general formula (Ffb):

wherein R⁴⁵ represents: a C1-6 alkoxycarbonyl group; phenyl group (whichmay be substituted on the phenyl ring by at least one group selectedfrom the group consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group); amino substituted C1-6 alkyl groupwhich may have, on the amino group, a group selected from a groupconsisting of a phenyl group (which may be substituted on the phenylring by at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group) and a C1-6alkyl group as a substituent; benzoyl group (which may be substituted onthe phenyl ring by at least one group selected from the group consistingof a halogen atom, a halogen-substituted or unsubstituted C1-6 alkylgroup, and a halogen-substituted or unsubstituted C1-6 alkoxy group);phenyl C1-6 alkyl group (which may be substituted on the phenyl ring byat least one group selected from the group consisting of a halogen atom,a halogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); phenyl C1-6alkoxycarbonyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); or phenyl C2-6alkenyl group (which may be substituted on the phenyl ring by at leastone group selected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group),

(F12-3) morpholino group;

(F12-4) imidazolyl group;

(F12-5) 1,4-dioxaazaspiro[4,5]decyl group (which may be substituted onthe 1,4-dioxaazaspiro[4,5]decane ring by at least one oxo group as asubstituent);

(F12-6) homopiperazinyl group (which may be substituted on thehomopiperazine ring by at least one group selected from the groupconsisting of a C1-6 alkoxycarbonyl group, a phenyl C1-6 alkoxycarbonylgroup, and a phenyl-substituted or unsubstituted phenyl group as asubstituent);

(F12-7) piperazinyl group (which may be substituted on the piperazinering by at least one group selected from the group consisting of an oxogroup, a C1-6 alkyl group, and a phenyl C1-6 alkyl group (which may besubstituted on the phenyl ring by at least one halogen-substituted orunsubstituted C1-6 alkyl group));

(F12-8) piperidyl group (which may be substituted on the piperidine ringby at least one oxo group as a substituent);

(F12-9) pyrrolidinyl group (which may be substituted on the pyrrolidinering by at least one phenoxy C1-6 alkyl group that may have ahalogen-substituted or unsubstituted C1-6 alkoxy group as asubstituent); and

(F12-10) isoindolinyl group,

F13) moreover, R¹⁹ and R²⁰ may bind to each other together with nitrogenatoms adjacent thereto directly or through hetero atoms, so as to form acyclic imide or amide shown in any one of (F13-1) to (F13-11) indicatedbelow:

(F13-1) succinimide group;

(F13-2) oxazolidinyl group (which may be substituted on the oxazolidinering by at least one oxo group as a substituent);

(F13-3) benzo-1,3-oxazolidinyl group (which may be substituted on thebenzo-1,3-oxazolidine ring by at least one group selected from the groupconsisting of an oxo group, a halogen atom, and a phenyl group as asubstituent);

(F13-4) imidazolidinyl group (which may be substituted on theimidazolidine ring by at least one group selected from the groupconsisting of an oxo group, a phenyl C1-6 alkyl group (which may besubstituted on the phenyl ring by 1 to 3 groups selected from the groupconsisting of a halogen atom and a C1-6 alkoxy group), and a phenylgroup);

(F13-5) benzimidazolidinyl group (which may be substituted on thebenzimidazolidine ring by at least one group selected from the groupconsisting of: an oxo group; a halogen atom; a halogen-substituted orunsubstituted C1-6 alkyl group; an amino group which may have a C1-6alkyl group as a substituent; a C1-6 alkoxycarbonyl group; and apiperidyl group (which may be substituted on the piperidine ring by atleast one group selected from the group consisting of a C1-6 alkylgroup, a phenyl group wherein 1 to 3 halogen atoms may be substituted onthe phenyl ring, a C1-6 alkoxycarbonyl group, and a phenyl C1-6alkoxycarbonyl group as a substituent));

(F13-6) phthalimide group;

(F13-7) indolinyl group (which may have on the indoline ring at leastone group selected from the group consisting of a C1-6 alkyl group, ahalogen atom, and an oxo group as a substituent);

(F13-8) 2,3-dihydrobenzothiazolyl group (which may have at least one oxogroup on the 2,3-dihydrobenzothiazole ring);

(F13-9) 1H-2,4-benzoxazinyl group (which may be substituted on the1H-2,4-benzoxazine ring by at least one oxo group as a substituent);

(F13-10) a group represented by the following general formula (Fga):

wherein R³⁹ represents: a hydrogen atom; a phenyl C1-6 alkyl group whichmay have, as a substituent, a halogen atom on the phenyl ring; phenoxyC1-6 alkyl group which may have, as a substituent, a halogen atom on thephenyl ring; phenyl C2-6 alkenyl group which may have, as a substituent,a halogen atom on the phenyl ring; phenyl group which may be substitutedon the phenyl ring by at least one group selected from the groupconsisting of a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, a halogen-substituted or unsubstituted C1-6 alkoxygroup, and a phenyl group as a substituent; pyridyl group; or pyrazinylgroup, and

(F13-11) 1,3-thiazolidinyl group (which may be substituted on the1,3-thiazolidine ring by at least one group selected from a groupconsisting of an oxo group and a phenyl C1-6 alkylidene group which mayhave a halogen-substituted or unsubstituted C1-6 alkyl group on thephenyl ring as a substituent),

a group represented by the following general formula (G):

wherein R⁴⁰ represents a C1-6 alkyl group, or halogen-substituted orunsubstituted phenyl group,

a spiro ring group represented by the following general formula (H):

wherein R⁴¹ represents:

H1) hydrogen atom;

H2) C1-6 alkyl group;

H3) phenyl C1-6 alkyl group that may have a phenyl group as asubstituent on the phenyl ring;

H4) phenyl group (which may be substituted on the phenyl ring by atleast one group selected from the group consisting of: a halogen atom; ahalogen-substituted or unsubstituted C1-6 alkyl group; ahalogen-substituted or unsubstituted C1-6 alkoxy group; an amino group(which may be substituted on the amino group by at least one groupselected from the group consisting of a C1-6 alkyl group and a phenylgroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group)); an phenoxygroup (which may be substituted on the phenyl ring by at least one groupselected from the group consisting of a halogen atom, ahalogen-substituted or unsubstituted C1-6 alkyl group, and ahalogen-substituted or unsubstituted C1-6 alkoxy group); and piperidylgroup (which may be substituted on the piperidine ring by at least onegroup selected from the group consisting of phenoxy groups (which may besubstituted on the phenyl ring by at least one group selected from thegroup consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, and a halogen-substituted orunsubstituted C1-6 alkoxy group) as a substituent));

H5) piperazinyl C1-6 alkyl group (which may be substituted on thepiperazine ring by at least one group selected from the group consistingof a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkoxycarbonyl group(which may be substituted on the phenyl ring by 1 to 3 groups selectedfrom the group consisting of a halogen atom, a halogen-substituted orunsubstituted C1-6 alkyl group, a halogen-substituted or unsubstitutedC1-6 alkoxy group, and a phenyl group);

H6) piperazinylcarbonyl C1-6 alkyl group (which may be substituted onthe piperazine ring by at least one group selected from the groupconsisting of: a C1-6 alkoxycarbonyl group; a phenyl C1-6 alkoxycarbonylgroup which may have, as a substituent, a halogen-substituted orunsubstituted C1-6 alkyl group on the phenyl ring; and a phenyl C1-6alkyl group which may have, as a substituent, at least one groupselected from the group consisting of a halogen-substituted orunsubstituted C1-6 alkyl group and a phenyl group on the phenyl ring);

H7) phenylcarbamoyl C1-6 alkyl group which may have at least onehalogen-substituted or unsubstituted C1-6 alkyl group as a substituenton the phenyl ring;

H8) benzoxazolyl C1-6 alkyl group (which may have at least one oxo groupas a substituent on the benzoxazole ring);

H9) benzothiazolyl group;

H10) tetrazolyl group (which may have at least one phenyl group as asubstituent on the tetrazole ring);

H11) C1-6 alkylsulfonyl group;

H12) phenylsulfonyl group which may have at least one C1-6 alkyl groupas a substituent on the phenyl ring;

H13) phenylthiocarbamoyl group which may be substituted on the phenylring by at least one halogen atom as a substituent;

H14) C1-8 alkoxycarbonyl group;

H15) phenyl C1-6 alkoxycarbonyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen atom, a C1-6 alkoxycarbonyl group, an amino group which mayhave a C1-6 alkoxycarbonyl group as a substituent, a halogen-substitutedor unsubstituted C1-6 alkyl group, a halogen-substituted orunsubstituted C1-6 alkoxy group, a nitro group, and a C1-6 alkylthiogroup);

H16) benzhydryloxycarbonyl group (which may be substituted on the phenylring by at least one halogen atom);

H17) C1-6 alkoxycarbonyl group which may have a phenyl-substituted orunsubstituted phenyl group;

H18) naphthyl C1-6 alkoxycarbonyl group;

H19) pyridyl C1-6 alkoxycarbonyl group;

H20) C1-6 alkoxy-substituted C1-6 alkoxycarbonyl group;

H21) piperazinyl C1-6 alkoxycarbonyl group (which may be substituted onthe piperazine ring by at least one group selected from the groupconsisting of a C1-6 alkoxycarbonyl group and a phenyl C1-6 alkyl group(which may have at least one halogen atom as a substituent on the phenylring) as a substituent);

H22) phenoxycarbonyl group (which may be substituted on the phenyl ringby at least one group selected from the group consisting of a C1-6 alkylgroup and a C1-6 alkoxy group);

H23) C1-6 alkanoyl group;

H24) benzoyl group (which may be substituted on the phenyl ring by atleast one halogen-substituted or unsubstituted C1-6 alkyl group);

H25) phenyl C1-6 alkanoyl group (which may be substituted on the phenylring by at least one halogen-substituted or unsubstituted C1-6 alkylgroup);

H26) phenoxy C1-6 alkanoyl group (wherein 1 to 3 halogen atoms may besubstituted on the phenyl ring);

H27) piperazinyl C2-6 alkanoyl group (which may be substituted on thepiperazine ring by at least one group selected from a group consistingof: a C1-6 alkanoyl group; a phenyl C1-6 alkyl group which may have, asa substituent, at least one group selected from the group consisting ofa phenyl group, a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup, on the phenyl ring; a phenyl C1-6 alkoxycarbonyl group which mayhave, as a substituent, at least one group selected from the groupconsisting of a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup, on the phenyl ring; a phenylcarbamoyl C1-6 alkyl group which mayhave, as a substituent, at least one group selected from the groupconsisting of a halogen atom, a halogen-substituted or unsubstitutedC1-6 alkyl group, and a halogen-substituted or unsubstituted C1-6 alkoxygroup, on the phenyl ring; a phenylcarbamoyl group which may have, as asubstituent, at least one group selected from the group consisting of ahalogen atom, a halogen-substituted or unsubstituted C1-6 alkyl group,and a halogen-substituted or unsubstituted C1-6 alkoxy group, on thephenyl ring; and a benzoxazolyl group);

H28) phenylcarbamoyl group (which may be substituted on the phenyl ringby 1 to 3 groups selected from the group consisting of a halogen atom,an amino group which may have a C1-6 alkyl group as a substituent, acarboxyl group, a C1-6 alkoxycarbonyl group, a halogen-substituted orunsubstituted C1-6 alkyl group, a halogen-substituted or unsubstitutedC1-6 alkoxy group, a piperazinyl group which may have a C1-6 alkyl groupas a substituent on the piperazine ring, and a morpholino group);

H29) phenyl C1-6 alkylcarbamoyl group (which may be substituted on thephenyl ring by at least one group selected from the group consisting ofa halogen-substituted or unsubstituted C1-6 alkyl group and ahalogen-substituted or unsubstituted C1-6 alkoxy group); or

H30) piperazinylcarbonyl group (which may be substituted on thepiperazine ring by at least one group selected from the group consistingof a C1-6 alkoxycarbonyl group, a phenyl C1-6 alkoxycarbonyl group whichmay have at least one halogen-substituted or unsubstituted C1-6 alkylgroup on the phenyl ring, and a phenyl C1-6 alkyl group which may have ahalogen-substituted or unsubstituted C1-6 alkyl group on the phenylring),

provided that, when R¹ represents a hydrogen atom and R² represents agroup represented by the above general formula (A), then R³ cannot be anisopropyl group; when R¹ represents a hydrogen atom, R² represents agroup represented by the above general formula (E), and m is 0, then R¹¹cannot be a hydrogen atom; and further, when R¹ represents a hydrogenatom and R² represents a group represented by the above general formula(F), then it is not possible that R¹⁹ represents a hydrogen atom and R²⁰represents a tert-butoxycarbonyl group.

Reaction of compound (10a) or (10b) with compound (28) is carried out ina suitable solvent or without solvent, the presence or absence of abasic compound.

As to the solvents to be used in this reaction, for example, water;alcohols, such as methanol, ethanol, isopropanol, n-butanol,tert-butanol and the like; aromatic hydrocarbons, such as benzene,toluene, xylene, tetraline, o-chlorobenzene, m-chlorobenzene,2,3-dichlorobenzene and the like; halogenated hydrocarbons, such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride andthe like; ethers, such as diethyl ether, dioxane, tetrahydrofuran,diglyme, dipropyl ether, dimethoxyethane and the like; saturatedhydrocarbons, such as n-butane, n-hexane, cyclohexane, liquid paraffinand the like; ketones, such as acetone, methyl ethyl ketone and thelike; polar solvents, such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoroustriamide, acetonitrile, 1-methyl-2-pyrrolidinone (NMP) and the like; andmixtures of these solvents can be exemplified.

As to the basic compounds, well-known inorganic basic compounds andorganic basic compounds can be widely used.

As to the inorganic basic compounds, for example, alkali metalcarbonates, such as sodium carbonate, potassium carbonate and the like;alkali metal hydrogencarbonates, such as sodium hydrogencarbonate,potassium hydrogencarbonate and the like; alkali metal hydroxide, suchas sodium hydroxide, potassium hydroxide and the like; alkali metalphosphates, such as sodium phosphate, potassium phosphate and the like;alkali metal hydrides, such as sodium hydride, potassium hydride and thelike: alkali metals, such as potassium, sodium and the like; alkalimetal amides, such as sodium amide and the like; alkali metalalcoholates, such as sodium methylate, sodium ethylate, sodiumtert-butoxide and the like can be exemplified.

As to the organic basic compounds, for example, acetates, such as sodiumacetate, potassium acetate and the like; pyridine, trimethylamine,triethylamine, diisopropylethylamine, dimethylaniline,1-methylpyrrolidine, N-methylmorpholine, N,N-dimethyl-4-aminopyridine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like can beexemplified.

The amount of compound (28) is generally at least about 1 molarquantity, preferably about 1 to 5 molar quantities per 1 mole ofcompound (10a) or compound (10b).

The amount of the basic compound is generally about 0.1 to 1 molarquantity, preferably about 0.1 to 0.5 molar quantity per 1 mole ofcompound (10a) or compound (10b).

Reaction of compound (10a) or compound (10b) with compound (28) iscarried out generally at a room temperature to 150° C., preferably abouta room temperature to 120° C., and is finished generally in about 10minutes to 24 hours.

Reaction of obtaining compound (30a) from compound (29a) and reaction ofobtaining compound (30b) from compound (29b) are carried out in asuitable solvent or without solvent, in the presence of a basiccompound.

As to the solvents and basic compound to be used herein, any solventsand basic compounds used in the above-mentioned reaction of compound(10a) or compound (10b) with compound (28) can also be used.

The amount of the basic compound is generally about at least 1 molarquantity, preferably 1 to 2 molar quantities per 1 mole of compound(29a) or compound (29b).

The said reaction is carried out generally at about 0 to 150° C.,preferably at about 0 to 120° C., and is finished generally in about 10minutes to 48 hours.

4-Nitroimidazole compound represented by the general formula (2) of thepresent invention can be also introduced to compound (38), being usefulas antitubercular agent described in WO97/01562 (Japanese PatentPublication Hei 11-508270).

[wherein X is an oxygen atom, a sulfur atom or NR₂ (wherein R₂ is ahydrogen atom, a lower alkyl group, an aryl group, a cycloalkyl group, aheterocyclic group, a substituted heterocyclic group, aheterocyclic-alkyl group, COR₃, SO₂R₄ or COR₄R₅; wherein R₃, R₄ and R₅are each independently selected from the group consisting of a hydrogenatom, a lower alkyl group, an aryl group, an alkylaryl group, analkoxyaryl group, an alkoxyalkoxyaryl group, an alkyl-heterocyclicgroup, and an alkoxy-heterocyclic group); n is 1, 2 or 3; Y and Z areeach independently selected from the group consisting of an oxygen atom,CH₂, CO, CR₄R₅ and NR₄ (wherein, R₄ and R₅ are the same as definedpreviously); provided that, when n is 2 or 3, then compound (38) mayhave some substituents as shown in the following general formulas (IIa)and (IIb),

[wherein, R₆, R₇, R₈ and R₉ are each independently selected from thegroup consisting of a hydrogen atom, a lower alkyl group, an aryl group,an alkylaryl group, an alkoxyalkyl group, an alkoxyalkylaryl group, analkoxyalkyl-heterocyclic group, an alkylarylalkylaryl group, analkylarylaryl group, an alkylcycloalkyl group, an alkoxyaryl group, analkyl-heterocyclic group and an alkoxy-heterocyclic group]. Compound(38) can be prepared, for example by the Reaction scheme-13 as follows.

[wherein, X and X¹ are the same as defined previously; R^(D′) and R^(E′)are each, tetrahydropyranyl group, a tri(lower alkyl)silyl group, alower alkanoyl group or a phenyl-lower alkyl group which may have loweralkoxy groups as the substituents in the phenyl ring; RF is asubstituted or unsubstituted arylalkyl group, an alkyl group, asubstituted or unsubstituted arylalkoxyalkyl group, or a substituted orunsubstituted heterocyclic alkyl group; R^(G′) is 3,4-dihydro-2H-pyranor R^(I)X¹ (X¹ is the same as defined previously and R^(I) is atri(lower alkyl)silyl group, a lower alkanoyl group or a phenyl-loweralkyl group which may have lower alkoxy groups as the substituents inthe phenyl ring].

As to the tri(lower alkyl)silyl group, a silyl group having 3substituents each of which is a straight chain or branched chain alkylgroup having 1 to 6 carbon atoms, for example, tert-butyldimethylsilyl,trimethylsilyl, n-butylethylmethylsilyl, tert-butyldipropylsilyl,n-pentyldiethylsilyl, n-hexylpropylmethylsilyl groups and the like canbe exemplified.

As to the lower alkanoyl group, a straight chain or branched chainalkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl,propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoylgroups and the like can be exemplified.

Reaction of compound (2) with compound (31a) and reaction of compound(2) with compound (31d) can be carried out under the condition similarto that employed in the reaction of compound of (4) with compound (9) inthe above-mentioned Reaction scheme-3 wherein X² is a halogen atom.

Reaction for obtaining compound (34) from compound (33b) and reactionfor obtaining compound (34a) from compound (33d) wherein R^(D′) is atri(lower alkyl)silyl group are carried out in a suitable solvent in thepresence of a desilylating agent. As to the solvent to be used, any oneof the solvent being used in the reaction for introducing compound (1a)to compound (2a) in the above-mentioned Reaction scheme-3 can be alsoused. As to the desilylating agent, an alkylammonium halide such astetrabutylammonium fluoride can be exemplified. The amount ofdesilylating agent may be at least an equimolar quantity, preferably 1to 2 molar quantities per 1 mole of compound (33b) or (33d). The saidreaction is carried out at 0-100° C., preferably 0-70° C., and isfinished in about 1 to 30 hours. When R^(D′) is a tetrahydropyranylgroup, a lower alkanoyl group or a phenyl-lower alkyl group which mayhave lower alkoxy group as the substituents in the phenyl group, thesaid reaction can be carried out under the condition similar to thatemployed in the reaction for obtaining compound (2a) from compound (1a)in the above-mentioned Reaction scheme-3.

Reaction of compound (2) with compound (31b) and reaction of compound(2) with compound (31c) can be carried out under the condition similarto that employed in the reaction of compound (4) with compound (9) inthe above-mentioned Reaction scheme-3, wherein X² is a halogen atom.

Reaction of compound (33a) with compound (32), and reaction of compound(33c) with compound (32), can be carried out under the condition similarto that employed in the reaction of compound (40a) with compound (32) inthe Reaction scheme-14 mentioned below.

Reaction for obtaining compound (35) from compound (34), reaction forobtaining compound (35a) from compound (34a), reaction for obtainingcompound (36) from compound (35), reaction for obtaining compound (36a)from compound (35a), reaction of compound (36) with compound (37) andreaction of compound (36a) with compound (37) can be carried out by themethod disclosed in the WO97/01562 (Japanese Patent Publication Hei11-508270).

Among compounds (33a), (33b), (33c), (33d), (34) and (34a), those of4-nitroimidazole derivatives wherein X is a bromine atom or a group ofthe formula —S(O)nR¹ (wherein R¹ and n are the same as definedpreviously) are novel compounds, useful for intermediates for synthesisof antitubercular agents.

The starting materials of compounds (31a) and (31d) can be prepared byReaction scheme-14 as follows.

[wherein, X¹, R^(D′), R^(G′) and R^(E′) are the same as definedpreviously].

Reaction of compound (39a) or compound (39b) with compound (32) andreaction of compound (40a) or compound (40b) with compound (32) can becarried out in a suitable solvent, when R^(G′) is 3,4-dihydro-2H-pyran.As to the solvents to be used in this reaction, any one of solvents usedin the reaction of compound (4) with compound (9) in the above-mentionedReaction scheme-3 can be used, wherein X² is a halogen atom. The saidreaction is generally carried out about at 0 to 100° C., preferably at 0to 70° C., and is finished in about 1 to 30 hours. The said reaction iscarried out advantageously by adding, as a catalyst, for example, amineral acid, such as hydrochloric acid, sulfuric acid or the like; anorganic acid, such as pyridinium p-toluenesulfonic acid or the like.When R^(G′) is R^(I)X¹, the reaction can be carried out under thecondition similar to that employed in the reaction of compound (4) withcompound (9) in the above-mentioned Reaction scheme-3, wherein X² is ahalogen atom.

In the reaction of compound (39a) or compound (39b) with compound (32)and reaction of compound (40a) or compound (40b) with compound (32),wherein R^(G′) is R^(I)X¹ and R^(I) is a tri(lower alkyl)silkyl group,compound (40a) and compound (40b) can be obtained by the reaction in thepresence of imidazole in a suitable solvent. As to the solvent to beused, any one of the solvent being used in the reaction of compound (4)with compound (9) in the above-mentioned Reaction scheme-3, wherein X²is a halogen atom.

The amount of compound (32) is generally at least 1 molar quantity,preferably 1 to 2 molar quantities per 1 mole of compound (39a) orcompound (39b), or compound (40a) or compound (40b). The amount ofimidazole is generally at least about 1 molar quantity, preferably about1 to 2 molar quantities per 1 mole of compound (39a) or compound (39b),or compound (40a) or compound (40b). The said reaction is carried outgenerally at about 0 to 100° C., preferably about 0 to 70° C., and isfinished generally in about 1 to 30 hours.

Each of the objective compounds obtained from the above-mentionedreactions can be separated from the reaction mixture by usual separationmeans, and are subjected to further purifications. As to such means ofseparation and purification, for example, distillation method,recrystallization method, column chromatography, ion-exchangechromatography, gel chromatography, affinity chromatography, preparativethin layer chromatography, solvent extraction method and the like can beexemplified.

Among 1-substituted-4-nitroimidazole compounds represented by thegeneral formula (1) of the present invention having the basic group canbe easily form a salt with a usual pharmacologically acceptable acid. Asto the acids, for example, inorganic acids, such as sulfuric acid,nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid andthe like; organic acids, such as acetic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid,fumaric acid, citric acid, succinic acid, malic acid, tartaric acid,malonic acid, lactic acid, benzoic acid and the like can be exemplified.

1-Substituted-4-nitroimidazole compounds represented by the generalformula (1) of the present invention involve stereoisomers and opticalisomers.

1-Substituted-4-nitroimidazole compounds represented by the generalformula (1) of the present invention are used advantageously asintermediates for synthesizing antitubercular agents as shown in theabove-mentioned Reaction scheme-12 and Reaction scheme-13.

1-Substituted-4-nitroimidazole compounds represented by the generalformula (10) of the present invention are prepared by using compound(11) as the starting material. By using compound (11) [i.e., compound(11a) or compound (11b)], the reaction with 4-nitroimidazole compound(2) is selectively occurred at the specific position (b) indicatedbelow, and as the result, compound (10) [compound (10a) or compound(10b)] of the present invention having high optical purity can beprepared in high yield by one process step.

[wherein, R^(B) and R^(C) are the same as defined previously].

According to the present invention, the objective 4-nitroimidazolecompound represented by the general formula (2a) can be prepared withoutby passing through intermediates having risk of explosion.

Preparation method of the present invention is a simple in operation andwithout requires complicated purification processes.

According to the present invention, high purity of the objective4-nitroimidazole of the general formula (2a) can be prepared in low costand high yield.

Therefore, the preparation methods of the present invention areindustrially quite advantageous.

EXAMPLES

The present invention will be explained by illustrating some examples asfollows.

Reference Example 1 Preparation of 2,5-dibromo-4-nitroimidazole

To a suspension of water (100 ml), 4-nitroimidazole (25 g) and sodiumhydrogencarbonate (40.87 g), was dropwisely added bromine (26.5 ml) atlower than 10° C., the reaction mixture was stirred at 25 to 30° C. for1 hour, and at 50 to 60° C. for 4 hours. Then concentrated hydrochloricacid was added to the reaction mixture at lower than 10° C. to adjust pH1, the crystals separated were collected by filtration, and were washedthoroughly with water. The crystals were dried at 50° C. under a reducedpressure for 24 hours, there was obtained 51.01 g (85.2%) of2,5-dibromo-4-nitroimidazole of pale yellow powdery product.

Reference Example 2 Preparation of2,5-dibromo-1-methoxymethyl-4-nitroimidazole

Under an ice-cooling condition, sodium hydride (3.56 g) was added to aN,N-dimethylformamide (100 ml) solution of 2,5-dibromo-4-nitroimidazole(20.08 g). 10 minutes later, being added dropwise chloromethylmethylether (6.75 ml) thereto at 10 to 15° C., then the reaction mixture wasturned back to a room temperature. After being stirred this reactionmixture for 5 hours, under an ice-cooling condition, sodium hydride(0.30 g) and chloromethylmethyl ether (0.56 ml) were added, furtherstirred at a room temperature for 1 hour. Then the reaction mixture wasice-cooled, water was added and extracted with ethyl acetate. Theorganic layer was washed with an aqueous solution being saturated withsodium chloride, dried over anhydrous sodium sulfate, then concentratedunder a reduced pressure. Thus obtained crude crystals were washed withdiisopropyl ether, and dried at 50° C. for 24 hours, there was obtained2,5-dibromo-1-methoxymethyl-4-nitroimidazole (19.68 g, yield: 84.3%) asyellow powder product.

Reference Example 3 Preparation of(S)-2-methylglycidyl-4-nitrobenzenesulfonate

Under cooling at −10° C., to a toluene (830 ml) solution of β-methallylalcohol (83.0 g), diisopropyl D-(−)-tartrate (16.19 g) and molecularsieves 4A (41.5 g) was added titanium tetraisopropoxide (17.0 ml), afterbeing stirred the reaction mixture at −10° C. for 30 minutes, 80% ofcumene hydroperoxide (415 ml) was added dropwise at −10° C. to −2° C.After being stirred the reaction mixture at 0° C. for 22 hours, excessof cumene hydroperoxide was reduced by adding dropwise trimethylphosphite (141.1 ml) at −20° C. to −5° C. The end point of this reducingreaction was confirmed by use of zinc iodide starch paper.

Triethylamine (219 ml) was added to the reaction mixture, then toluene(830 ml) solution of 4-nitrobenzenesulfonyl chloride (332 g) was addeddropwise at −30° C. to −16° C., and stirred at −10° C. for 1 hour. Thereaction suspension was subjected to filtration with celite, and thefiltrate was washed with an aqueous solution of 15% tartaric acid, anaqueous solution being saturated with sodium hydrogencarbonate, and anaqueous solution being saturated with sodium chloride in this order.After being dried the organic layer over anhydrous magnesium sulfate,and concentrated under a reduced pressure to obtain brown oil product(695 g). To the thus obtained brown oil was crystallized by addingdiisopropyl ether (3,320 ml), the crystals were collected by filtrationand purified by use of a silica gel column chromatography (eluent:dichloromethane), then recrystallized from diisopropyl ether/ethylacetate (5/1) to obtain the desired compound (119.1 g, yield: 37.9%) aspale yellow crystals. Melting point: 71-72° C.

¹H-NMR (CDCl₃) δ (ppm): 1.38 (3H, s), 2.67 (1H, d, J=4.8 Hz), 2.72 (1H,d, J=4.5 Hz), 4.03 (1H, d, J=11.1 Hz), 4.27 (1H, d, J=11.1 Hz),8.10-8.15 (2H, m), 8.39-8.44 (2H, m).

Optical purity: 96.6% e.e. (enantiomeric excess)

The optical purity was determined by a high performance liquidchromatography (HPLC) under the following conditions:

Column: CHIRALPAK AD (4.6 mmφ×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/isopropanol=800/200

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Reference Example 4 Preparation of(R)-2-methylglycidyl-4-nitrobenzenesulfonate

To a toluene (100 ml) solution of β-methallyl alcohol (10.0 g),diisopropyl L-(+)-tartrate (1.95 g), molecular sieves 3A (5.13 g) wasadded dropwise titanium tetraisopropoxide (2.0 ml) under cooling at −15°C., and was stirred at −10° C. for 30 minutes, then 80% cumenehydroperoxide (49.6 ml) was added dropwise at −10° C. to −2° C. Afterbeing stirred the reaction mixture at −5° C. for 18 hours, excessivecumene hydroperoxide was reduced by adding dropwise trimethyl phosphite(18.1 ml) at −10° C. to −2° C. The end point of this reducing reactionwas confirmed by use of zinc iodide-starch paper.

To the reaction mixture was added a toluene (20 ml) solution oftriethylamine (23.3 ml) and N,N-dimethyl-4-aminopyridine (1.02 g), thena toluene (80 ml) solution of 4-nitrobenzenesulfonyl chloride (35.15 g)was added dropwise at −10° C. to −2° C., and was stirred at −5° C. for 3hours. The reaction suspension was subjected to filtration with celite,the filtrate was washed with an aqueous solution of 15% tartaric acid,an aqueous solution being saturated with sodium hydrogencarbonate, andan aqueous solution being saturated with sodium chloride in this order.After being dried the organic layer over anhydrous magnesium sulfate,and concentrated under a reduced pressure to obtain brown oil product(101.1 g).

To the thus obtained brown oil was crystallized by adding n-hexane (100ml), the crystals were collected by filtration. The filtered crystalswere recrystallized from diisopropyl ether/ethyl acetate (5/1) to obtain18.6 g (48.9%) of the desired compound of pale yellow crystals. Meltingpoint: 71-72° C.

¹H-NMR (CDCl₃) δ (ppm): 1.38 (3H, s), 2.67 (1H, d, J=4.8 Hz), 2.72 (1H,d, J=4.5 Hz), 4.03 (1H, d, J=11.1 Hz), 4.27 (1H, d, J=11.1 Hz),8.10-8.15 (2H, m), 8.39-8.44 (2H, m)

Optical purity: 97.0% e.e.

The optical purity was determined by a high performance liquidchromatography (HPLC) under the following conditions:

Column: CHIRALPAK AD (4.6 mmφ×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/isopropanol=800/200

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Reference Example 5 Preparation of(R)-2-methylglycidyl-3-nitrobenzenesulfonate

To a toluene (200 ml) solution of β-methallyl alcohol (10.0 g),diisopropyl L-(+)-tartrate (3.89 g) and molecular sieves 4A (10.0 g) wasadded dropwise titanium tetraisopropoxide (4.07 ml) under cooling at −5°C., and was stirred at −5° C. for 30 minutes, then 80% cumenehydroperoxide (49.6 ml) was added dropwise at −13° C. to −10° C. Afterbeing stirred the reaction mixture at −10° C. for 3.5 hours, excessivecumene hydroperoxide was reduced by adding dropwise trimethyl phosphite(18.1 ml) at −15° C. to −5° C. The end point of this reducing reactionwas confirmed by use of zinc iodide-starch paper.

To the reaction mixture was added a methylene chloride (10 ml) solutionof N,N-dimethyl-4-aminopyridine (2.0 g) and triethylamine (23.2 ml),then a methylene chloride (50 ml) solution of 3-nitrobenzenesulfonylchloride (33.9 g) was added dropwise at −15° C. to −5° C., and wasstirred at −10° C. for 17 hours. The reaction suspension was subjectedto filtration with celite, the filtrate was washed with an aqueoussolution of 15% tartaric acid, an aqueous solution being saturated withsodium hydrogencarbonate, and an aqueous solution being saturated withsodium chloride in this order. After being dried the organic layer overanhydrous magnesium sulfate, and concentrated under a reduced pressureto obtain brown oil product (129.2 g).

To the thus obtained brawn oil product was purified by a silia gelcolumn chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain(R)-2-methylglycidyl-3-nitrobenzenesulfonate of pale yellow oil (24.14g, yield: 63.5%).

¹H-NMR (CDCl₃) δ (ppm): 1.38 (3H, s), 2.67 (1H, d, J=4.8 Hz), 2.73 (1H,d, J=4.8 Hz), 4.05 (1H, d, J=11.0 Hz), 4.28 (1H, d, J=11.0 Hz), 7.81(1H, d, J=8.2, 7.8 Hz), 8.26 (1H, ddd, J=7.8, 1.8, 1.0 Hz), 8.53 (1H,ddd, J=8.2, 2.1, 1.0 Hz), 8.78 (1H, dd, J=2.1, 1.8 Hz).

Optical purity: 92.6% e.e.

The optical purity was determined by a high performance liquidchromatography (HPLC) under the following conditions:

Column: CHIRALPAK AD (4.6 mmφ×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/isopropanol=850/150

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Example 1 Synthesis of 2-bromo-1-methoxymethyl-4-nitroimidazole

Suspension of 2,5-dibromo-1-methoxymethyl-4-nitroimidazole (17.15 g),sodium sulfite (13.73 g), dimethylformamide (100 ml) and water (50 ml)was stirred at a room temperature for 8 hours. The reaction mixture wasneutralized with an aqueous solution being saturated with sodiumhydrogencarbonate, then ethyl acetate and water were added. The organiclayer was washed with an aqueous solution being saturated with sodiumchloride, and dried over anhydrous sodium sulfate, then concentratedunder a reduced pressure to obtain2-bromo-1-methoxymethyl-4-nitroimidazole (11.17 g, yield: 86.8%) ofwhite powdery product.

EI (m/z) M⁺: 235, 237

¹H-NMR (CDCl₃) δ (ppm): 7.93 (s, 1H), 5.34 (s, 2H), 3.41 (s, 3H).

Example 2 Synthesis of 2-bromo-4-nitroimidazole

Solution of 2-bromo-1-methoxymethyl-4-nitroimidazole (11.17 g), methanol(10 ml) and 5N hydrochloric acid (60 ml) was stirred under refluxingcondition for 2.5 hours. After being let to stand the reaction mixtureat a room temperature for 24 hours, the mixture was stirred for 1 hourunder ice-cooling condition, the precipitated crystals were collected byfiltration, and dried at 50° C. under a reduced pressure for 24 hours,there was obtained 2-bromo-4-nitroimidazole (6.0 g, yield: 66.0%) ofwhite powdery product.

¹H-NMR (DMSO-d₆) δ (ppm): 8.42 (s, 1H), 14.10 (bs, 1H).

Example 3 Synthesis of 2-bromo-4-nitroimidazole

Into 1,4-dioxane (1 ml) solution of tetra-n-butylammonium borohydride(638 mg) was added dropwise 1,4-dioxane (1 ml) solution of2,5-dibromo-4-nitroimidazole (89.5 mg) at a room temperature, afterbeing refluxed the reaction mixture for 23 hours, excessive reagentswere quenched by adding concentrated hydrochloric acid, then water andethyl acetate were added. The organic layer was washed with an aqueoussolution being saturated with sodium chloride, then dried over anhydroussodium sulfate, and purified by a thin layer chromatography (developingagent: ethyl acetate) to obtain 2-bromo-4-nitroimidazole (44.9 g, yield:71%) of white powdery product.

¹H-NMR (DMSO-d₆) δ (ppm): 8.42 (s, 1H), 14.10 (bs, 1H)

Example 4 Preparation of(S)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole

To N,N-dimethylformamide (2.5 ml) solution of(R)-2-methylglycidyl-4-nitrobenzenesulfonate (0.5 g, 96.5% e.e.) wereadded 2-chloro-4-nitro-1H-imidazole (0.324 g) and potassium carbonate(0.330 g) at a room temperature. After being stirred the reactionmixture at 50° C. for 4 hours, the mixture was cooled to a roomtemperature, and was poured in water to cease the reaction. Extractedwith ethyl acetate, and the extract was washed with water and an aqueoussolution being saturated with sodium chloride in this order, then driedover anhydrous magnesium sulfate, and concentrated under a reducedpressure to obtain yellow solid product.

The thus obtained yellow solid product was purified by use of a silicagel column chromatography (eluent: n-hexane/ethyl acetate=7/3), therewas obtained (S)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole(0.341 g, yield: 85.6%) as pale yellow crystals.

Melting point: 65.5-67.0° C.

¹H-NMR (CDCl₃) δ (ppm): 1.39 (3H, s), 2.62 (1H, d, J=3.6 Hz), 2.79 (1H,d, J=3.6 Hz), 3.99 (1H, d, J=14.7 Hz), 4.38 (1H, d, J=14.7 Hz), 7.87(1H, s).

Optical purity: 95.4% e.e.

The optical purity was determined by use of high performance liquidchromatography (HPLC) under the following conditions.

Column: CHIRALPAK AD (4.6 mmφ×250 mm).

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/ethanol=850/150

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Example 5 Preparation of(S)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole

To N,N-dimethylformamide (2.5 ml) solution of(R)-2-methylglycidyl-3-nitrobenzenesulfonate (0.5 g, 92.6% e.e.) wereadded 2-chloro-4-nitroimidazole (0.270 g) and potassium carbonate (0.330g) at a room temperature. After being stirred the reaction mixture at50° C. for 3 hours, the mixture was cooled to a room temperature, andwas poured in water to cease the reaction. Reaction mixture wasextracted with ethyl acetate, and the extract was washed with water andan aqueous solution being saturated with sodium chloride in this order,then dried over anhydrous magnesium sulfate, and concentrated under areduced pressure to obtain yellow solid product.

The thus obtained yellow solid was purified by use of a silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=7/3), to obtain(S)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (0.307 g,yield: 77.0%) as pale yellow crystals.

Melting point: 65.5-67.0° C.

¹H-NMR (CDCl₃) δ (ppm): 1.39 (3H, s), 2.62 (1H, d, J=3.6 Hz), 2.79 (1H,d, J=3.6 Hz), 3.99 (1H, d, J=14.7 Hz), 4.38 (1H, d, J=14.7 Hz), 7.87(1H, s).

Optical purity: 91.9% e.e.

The optical purity was determined by use of high performance liquidchromatography (HPLC) under the following conditions.

Column: CHIRALPAK AD (4.6 mmφ×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/ethanol=850/150

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Example 6 Preparation of(R)-2-bromo-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole

Suspension of 2-bromo-4-nitroimidazole (100 g),2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (142.4 g),potassium carbonate (93.6 g), cesium fluoride (15.8 g) anddimethylformamide (420 ml) was stirred at 35-40° C. for 26 hours. Thereaction mixture was poured into water (1.2 liters), then extractedtwice with ethyl acetate (1 liter). The ethyl acetate layers werecombined together, after being washed twice with water (1.2 liters),further washed with an aqueous solution (800 ml) being saturated withsodium chloride, then dried over anhydrous magnesium sulfate. Afterbeing filtrated under reduced pressure, the filtrate was concentratedunder a reduced pressure. The thus obtained residue was purified by useof a silica gel column chromatography (eluent: n-hexane/ethylacetate=1/1), there was obtained(R)-2-bromo-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (110.9 g,yield: 81%) as yellow powdery product.

Melting point: 93.0-94.0° C.

¹H-NMR (CDCl₃) δ (ppm): 1.38 (3H, s), 2.61 (1H, d, J=4.0 Hz), 2.78 (1H,d, J=4.0 Hz), 4.00 (1H, d, J=14.9 Hz), 4.38 (1H, d, J=14.9 Hz), 7.92(1H, s).

Optical purity: 96.6% e.e.

The optical purity was determined by use of high performance liquidchromatography (HPLC) under the following conditions.

Column: CHIRALPAK AD (4.6 mmφ×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/ethanol=4/1

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Example 7 Preparation of(R)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole

To N,N-dimethylformamide (100 ml) solution of(S)-2-methylglycidyl-4-nitrobenzenesulfonate (50.0 g, 97.8% e.e.) wasadded 2-chloro-4-nitroimidazole (26.99 g) and potassium carbonate (27.82g) at a room temperature. After being stirred this reaction mixture at50° C. for 9 hours, the mixture was cooled to a room temperature, thenethyl acetate (150 ml) was added, after being removed the insolublematters by filtration, the mixture was washed with water and an aqueoussolution being saturated with sodium chloride in this order. Ethylacetate layer was dried over anhydrous magnesium sulfate, then wasconcentrated under a reduced pressure to obtain pale brown solid product(38.2 g).

The thus obtained pale brown solid was dissolved in toluene (380 ml),next silica gel (7.6 g) was added, after being stirred at a roomtemperature, the silica gel was removed by filtration. This treatmentwas repeated twice, then the mother liquor was concentrated, the residuewas crystallized by adding diisopropyl ether, there was obtained(R)-2-chloro-1-(2-methyloxiranylmethyl)-4-nitroimidazole (25.54 g,yield: 64.1%) as pale yellow crystals.

Melting point: 65.5-67.0° C.

¹H-NMR (CDCl₃) δ (ppm): 1.39 (3H, s), 2.62 (1H, d, J=3.6 Hz), 2.79 (1H,d, J=3.6 Hz), 3.99 (1H, d, J=14.7 Hz), 4.38 (1H, d, J=14.7 Hz), 7.87(1H, s).

Optical purity: 95.9% e.e.

The optical purity was determined by use of a high performance liquidchromatography (HPLC) under the following conditions.

Column: CHIRALPAK AD (4.6 mm×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Ltd.]

Moving bed: n-hexane/ethanol 850/150

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Reference Example 6 Preparation of(S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol

Mixture of (R)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole(2.50 g, 11.5 mM) obtained in example 7 and 4-(4-trifluoromethoxyphenyl)piperazine (3.11 g, 12.6 mM) in N,N-dimethylformamide (25 ml) wasstirred at 70° C. for 7 hours. The temperature of reaction mixture wasturned back to a room temperature, water was added and extracted twicewith ethyl acetate. The organic layers were combined, washed with waterthree times, dried on anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated under a reduced pressure, there was obtained(S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol(5.55 g, yield: 100%) of slightly yellow oily product.

¹H-NMR (CDCl₃) δ (ppm): 1.18 (3H, s), 2.41 (1H, d, J=13.8 Hz), 2.56 (1H,d, J=13.8 Hz), 2.67-2.80 (2H, m) 2.85-2.96 (2H, m), 3.13-3.25 (4H, m),4.03 (2H, s) 6.83-6.93 (2H, m), 7.07-7.17 (2H, m), 8.0.7 (1H, s).

Reference Example 7 Preparation of(S)-2-[4-(4-trifluoromethoxyphenyl)piperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole

Under ice-cooling condition, to THF (150 ml) solution of(S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol(5.85 g, 12.61 mM) obtained in Reference example 6, was added sodiumhydride (0.76 g, 18.92 mM), then the reaction mixture was heated andrefluxed for 6 hours. The reaction mixture was concentrated under areduced pressure, then subjected to ice-cooling, and water and ethylacetate were added, the precipitated matters were collected byfiltration, and purified by using a silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/1), and recrystallized fromisopropanol, there was obtained(S)-2-[4-(4-trifluoromethoxyphenyl)piperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole(2.58 g, yield: 48%) of slightly yellow solid.

Optical purity: 99.8% e.e.

[α]_(D) ²⁶=8.80° (c: 1.000, CHCl₃)

Melting point: 129-130° C.

Test Example 1 Antibiotic Test by Using an Agar Plate Dilution Method

Minimum inhibitory concentration of(S)-2-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazoleobtained in reference example 7 against strain of Mycobacteriumtuberculosis H37RV was determined by using Culture medium 7H11(manufactured by BBL Co.). The above-mentioned strain was cultivatedpreviously in Culture medium 7H9 (manufactured by BBL Co.), the numberof living bacteria of the strain was counted out, the culture medium wasfreeze-storaged at −80° C. was used, the final number of living bacteriawas adjusted to about 10⁶ CFU/ml. Thus prepared culture medium (5 μl)was inoculated on Culture medium 7H11 containing test compound, andcultivated at 37° C. for 14 days, the said cultivated medium was used tothe test for determining the minimum inhibitory concentration.

The minimum inhibitory concentration of the test compound againstMycobacterium tuberculosis H37RV was 0.024 μg/ml.

Reference Example 8 Preparation of N-(diethoxymethyl)imidazole

Mixture of imidazole (13.6 g), triethyl orthoformate (133 ml) andp-toluenesulfonic acid monohydrate (1.00 g) was stirred by heating at140° C. for 2 hours. Reaction mixture was subjected to distillationunder a reduced pressure, there was obtained N-(diethoxymethyl)imidazole(22.8 g, yield: 67.0%) as colorless oily product.

Boiling point: 106-108° C. (at 1 torr).

Reference Example 9 Preparation of 2-chloroimidazole

N-(Diethoxymethyl)imidazole (50.0 g) was dissolved in tetrahydrofuran(200 ml), to this solution was added dropwise n-hexane solution (120 ml)of 2.6M n-butyllithium at lower than −35° C., next tetrahyfrofuransolution (100 ml) of hexachloroethane (73.9 g) was added dropwise.Reaction mixture was allowed to stand at the same temperature for 5minutes, then temperature was rised, after being added 6N hydrochloricacid (100 ml) at −20° C., then turned back to room temperature, andallowed to stand for 5 minutes. The aqueous layer was taken byseparation, and the organic layer was extracted with 1N hydrochloricacid, the extract was combined with the former aqueous layer, and washedwith diethyl ether, then neutralized with an aqueous solution of 6Nsodium hydroxide, and extracted with ethyl acetate. The organic layerwas taken by separation, after being dried over anhydrous magnesiumsulfate, the solvent was removed by distillation to obtained a crudeproduct. This crude product was triturated with methylene chloride,there was obtained 2-chloroimidazole (26.0 g, yield: 85.0%) aspale-brown solid product.

¹H-NMR (CDCl₃) δ (ppm): 10.64 (1H, bs), 7.05 (1H, s).

Reference Example 10 Preparation of 2-chloro-4,5-diiodoimidazole

2-Chloroimidazole (5.13 g) was suspended in water (150 ml), and anaqueous solution of 6N sodium hydroxide (17 ml) was added. Next, iodine(25.9 g) was added and was stirred at a room temperature for 3 hours.After that, the reaction mixture was treated with an aqueous solution ofsodium sulfite, the deposited matters were collected by filtration anddried, there was obtained 2-chloro-4,5-diiodoimidazole (16.4 g, yield:92.5%) as yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 13.61 (1H, bs).

¹³C-NMR (DMSO-d₆) δ (ppm): 133.07.

Reference Example 11 Preparation of 2-chloro-4-iodoimidazole

2-Chloro-4,5-diiodoimidazole (7.09 g) and sodium sulfite (20.2 g) weredissolved in 30% ethanol (50 ml), the solution was heated and refluxedfor 5 hours. Then the reaction mixture was concentrated, to the residuethus obtained was added water and the deposited matters were collectedby filtration, and was triturated with diluted hydrochloric acid, therewas obtained 2-chloro-4-iodoimidazole (885 mg, yield: 19.5%) as palebrown solid product.

¹H-NMR (DMSO-d₆) δ (ppm): 7.34 (1H, s).

Reference Example 12 Preparation of 2-chloro-5-iodo-4-nitroimidazole

2-Chloro-4,5-diiodoimidazole (354 mg) was suspended in concentratednitric acid (d. 1.42) (5 ml), under ice-cooling, concentrated sulfuricacid (1 ml) was added, and was stirred at a room temperature for 15hours. Reaction mixture was poured in ice-water, and ammonia water wasadded to adjust pH 3, the deposited matters were collected by filtrationand dried, there was obtained 2-chloro-5-iodo-4-nitroimidazole (222 mg,yield: 81.2%) as yellow solid product.

E1 (m/z) M⁺=273.

Reference Example 13 Preparation of 2-chloro-5-iodo-4-nitroimidazole

2-Chloro-4-iodoimidazole (431 mg) was suspended in concentrated nitricacid (d. 1.38) (2.5 ml), under ice-cooling, concentrated sulfuric acid(2.5 ml) was added, and stirred at a room temperature for 6 hours. Then,the deposited matters were collected by filtration, and dried, there wasobtained 2-chloro-5-iodo-4-nitroimidazole (348 mg, yield: 67.0%) asyellow solid product.

Reference Example 14 Preparation of 2-(4-nitrophenylthio)imidazole

Acetonitrile (100 ml) suspension of 2-mercaptoimidazole (5.0 g) and4-chloronitrobenzene (8.7 g), potassium carbonate (8.3 g) was stirredunder refluxing for 1 day. The reaction mixture was poured intoice-water. The deposited solid matters were collected by filtration,washed with water and diethyl ether. The thus obtained solids weredried, there was obtained 2-(4-nitrophenylthio)imidazole (9.5 g, yield:86%) as yellow powdery product.

¹H-NMR (DMSO-d₆) δ (ppm): 7.22 (2H, d, J=9.0 Hz), 7.34 (2H, br.s), 8.14(2H, d, J=9.0 Hz), 13.06 (1H, br.s).

Reference Example 15 Preparation of2-(2-chloro-6-nitrophenylthio)imidazole

Acetonitrile (20 ml) suspension of 2-mercaptoimidazole (1.0 g) and2,3-dichloronitrobenzene (2.1 g), potassium carbonate (1.7 g) wasstirred under refluxing for 6.5 hours. The reaction mixture was pouredinto ice-water. The deposited solids were collected by filtration, andwashed with n-hexane. The thus obtained solids were dried, there wasobtained 2-(2-chloro-6-nitrophenylthio)imidazole (2.4 g, yield: 94%) asyellow powdery product.

¹H-NMR (DMSO-d₆) δ (ppm): 6.75-7.33 (1H, m), 7.64 (1H, t, J=8.0 Hz),7.87 (1H, dd, J=1.0, 8.0 Hz), 7.97 (1H, dd, J=1.0, 8.0 Hz), 12.55 (1H,br.s).

Reference Example 16 Preparation of1-nitro-2-(4-nitrophenylthio)imidazole

To chloroform (15 ml) suspension of 2-(4-nitrophenylthio)imidazole (1.0g) and tetra-n-butylammonium nitrate (2.1 g) was added dropwisechloroform (5 ml) solution of anhydrous trifluoroacetic acid (1.3 ml) at−10° C., the reaction mixture was stirred at the same temperature for 25minutes. Ice-water was added to the reaction mixture, after beingstirred for a while, dichloromethane was added, and the dichloromethanelayer was taken by separation, and washed with water, an aqueoussolution being saturated with sodium hydrogencarbonate, and an aqueoussolution being saturated with sodium chloride, then dried over anhydroussodium sulfate. The residue obtained by removal of the solvent bydistillation was purified by use of a silica gel column chromatography(eluent: n-hexane/ethyl acetate=4/1), there was obtained1-nitro-2-(4-nitrophenylthio)imidazole (1.0 g, yield: 84%) as yellowpowdery product.

¹H-NMR (CDCl₃) δ (ppm): 6.91 (1H, d, J=2.0 Hz), 7.82 (1H, d, J=2.0 Hz),7.84 (2H, d, J=8.8 Hz), 8.30 (2H, d, J=8.8 Hz).

Reference Example 17 Preparation of 1-nitro-2-(2-nitrophenylthio)imidazole

To chloroform (10 ml) suspension of 2-(2-nitrophenylthio)imidazole (500mg) and tetra-n-butylammonium nitrate (1.0 g) was added anhydroustrifluoroacetic acid (0.64 ml) at −20° C., then the reaction mixture wasstirred at −10° C. for 30 minutes. To the reaction mixture was addedice-water, after being stirred for a while, ethyl acetate was added andthe organic layer was taken by separation. The ethyl acetate layer waswashed with water, an aqueous solution being saturated with sodiumhydrogencarbonate and an aqueous solution being saturated with sodiumchloride, then dried over anhydrous sodium sulfate. The residue obtainedby removal of the solvent by distillation was purified by use of asilica gel column chromatography (eluent: n-hexane/ethyl acetate=13/7),there was obtained 1-nitro-2-(2-nitrophenylthio) imidazole (510 mg,yield: 87%) as yellow powdery product.

¹H-NMR (CDCl₃) δ (ppm): 6.98 (1H, d, J=2.0 Hz), 7.49-7.69 (3H, m), 7.85(1H, d, J=2.0 Hz), 8.11-8.19 (1H, m).

Reference Example 18 Preparation of2-(2-chloro-6-nitrophenylthio)-1-nitroimidazole

To chloroform (10 ml) suspension of2-(2-chloro-6-nitrophenylthio)imidazole (500 mg) and tetra-n-butylammonium nitrate (893 mg) was added anhydrous trifluoroacetic acid (0.55ml) at −20° C., then stirred at −10° C. for 3 hours. Ice-water was addedto the reaction mixture, and after being stirred for a while, ethylacetate was added, and the organic layer was taken by separation. Theethyl acetate layer was washed with water, an aqueous solution beingsaturated with sodium hydrogencarbonate, an aqueous solution beingsaturated with sodium chloride, then dried over anhydrous sodiumsulfate. The residue obtained by removal of the solvent by distillationwas purified by use of a silica gel column chromatography (eluent:n-hexane/ethyl acetate=13/7), there was obtained2-(2-chloro-6-nitrophenylthio)-1-nitroimidazole (506 mg, yield: 85%) asyellow powdery product.

¹H-NMR (CDCl₃) δ (ppm): 6.85 (1H, d, J=2.0 Hz), 7.60 (1H, t, J=8.0 Hz),7.74 (1H, d, J=2.0 Hz), 7.80 (1H, dd, J=1.3, 8.0 Hz), 7.81 (1H, dd,J=1.3, 8.0 Hz).

Reference Example 19 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-2-(4-nitrophenylthio) imidazole

To N,N-dimethylformamide (5 ml) solution of2-(4-nitrophenylthio)imidazole (500 mg) was added sodium hydride (90 mg)at 0° C., then reaction mixture was stirred at a room temperature for 30minutes. After being cooled again the reaction mixture to 0° C.,2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (618 mg) was addedand stirred at a room temperature for 3.5 hours. Water and ethyl acetatewere added to the reaction mixture, the organic layer was taken byseparation. The ethyl acetate layer was washed with water and an aqueoussolution being saturated with sodium chloride, then dried over anhydroussodium sulfate. The residue obtained by removal of the solvent bydistillation was purified by use of a silica gel column chromatography(eluent: dichlormethane/ethyl acetate=17/3), there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-2-(4-nitrophenylthio)imidazole (604mg, yield: 91%) as yellow oily product.

¹H-NMR (CDCl₃) δ (ppm): 1.21 (3H, s), 2.52 (1H, d, J=4.3 Hz), 2.63 (1H,d, J=4.3 Hz), 3.98 (1H, d, J=14.8 Hz), 4.39 (1H, d, J=14.8 Hz), 7.21(2H, d, J=9.0 Hz), 7.32 (1H, d, J=1.3 Hz), 7.34 (1H, J=1.3 Hz), 8.10(2H, d, J=9.0 Hz).

Reference Example 20 Preparation of1-(2-cyanoethyl)-2-(4-nitrophenylthio)-imidazole

To acrylonitrile (10 ml) suspension of 2-(4-nitrophenylthio)imidazole(500 mg) was added 1,8-diazabicyclo[5.4.0]undecene-7 (0.04 ml), thereaction mixture was stirred for 1 hour under refluxing. The residueobtained by concentration was purified by use of a basic silica gelcolumn chromatography (eluent: dichloromethane), the thus obtained solidwas recrystallized from dichloromethane-tert-butylmethyl ether, therewas obtained 1-(2-cyanoethyl)-2-(4-nitrophenylthio)imidazole (454 mg,yield: 74%) as colorless granular product.

¹H-NMR (CDCl₃) δ (ppm): 2.72 (2H, t, J=6.8 Hz), 4.35 (2H, t, J=6.8 Hz),7.20 (2H, d, J=9.0 Hz), 7.34 (1H, d, J=1.3 Hz), 7.38 (1H, d, J=1.3 Hz),8.13 (2H, d, J=9.0 Hz).

Reference Example 21 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazine-1-carboxylate

N,N-Dimethylformamide (0.5 ml) solution of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole(100 mg) and 3-(4-trifluoromethylphenyl)-2-propenylpiperazine-1-carboxylate (103 mg) was stirred at 60° C. for 1 day. Waterand ethyl acetate were added to the reaction mixture, and the organiclayer was taken by separation. The ethyl acetate layer was washed withwater and an aqueous solution being saturated with sodium chloride, thendried over anhydrous sodium sulfate. The residue obtained by removal ofthe solvent by distillation was purified by use of a silica gel columnchromatography (eluent: dichloromethane/methanol=50/1 to 30/1) and abasic silica gel column chromatography (eluent: dichlormethane), therewas obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate(173 mg, yield: 90%) as pale yellow amorphous product.

¹H-NMR (DMSO-d₆) δ (ppm): 1.01 (3H, s), 2.25-2.64 (6H, m), 3.15-3.50(4H, m), 4.12 (1H, d, J=14.0 Hz), 4.35 (1H, d, J=14.0 Hz), 4.71 (2H, d,J=5.3 Hz), 5.00 (1H, s), 6.55 (1H, td, J=5.3, 16.0 Hz), 6.74 (1H, d,J=16.0 Hz), 7.49 (2H, d, J=9.0 Hz) 7.69 (4H, s), 8.18 (2H, d, J=9.0 Hz),8.55 (1H, s).

Reference Example 22 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl)piperazin-1-carboxylate

N,N-Dimethylformamide (0.25 ml) solution of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(2-nitrophenylthio)imidazole(50 mg) and 3-(4-trifluoromethylphenyl)-2-propenylpiperazin-1-carboxylate (51 mg) was stirred at 60° C. for 1 day. Waterand ethyl acetate were added to the reaction mixture, the organic layerwas taken by separation. The ethyl acetate layer was washed with water,an aqueous solution being saturated with sodium chloride, then driedover anhydrous sodium sulfate. The residue obtained by removal of thesolvent by distillation was purified by use of a thin layerchromatography (eluent: dichloromethane/methanol=30/1), there wasobtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate(86 mg, yield: 87%) as yellow amorphous product.

¹H-NMR (CDCl₃) δ (ppm): 1.08 (3H, s), 2.29 (1H, d, J=14.0 Hz), 2.40-2.71(5H, m, including 2.44, d, J=14.0 Hz), 3.20 (1H, br.s), 3.50 (4H, br.s),4.09 (2H, s), 4.77 (2H, d, J=6.0 Hz), 6.39 (1H, td, J=6.0, 16.0 Hz),6.65 (1H, d, J=16.0 Hz), 6.96 (1H, dd, J=1.0, 8.0 Hz), 7.39 (1H, dt,J=1.0, 8.0 Hz), 7.46-7.53 (3H, m, including 7.49, d, J=8.0 Hz), 7.58(2H, d, J=8.0 Hz), 8.27 (1H, dd, J=1.0, 8.0 Hz), 8.30 (1H, s).

Reference Example 23 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate

N,N-Dimethylformamide (0.25 ml) solution of(R)-2-(2-chloro-6-nitrophenylthio)-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole(55 mg) and 3-(4-trifluoromethylphenyl)-2-propenylpiperazin-1-carboxylate (51 mg) was stirred at 60° C. for 1 day. To thereaction mixture was added water and ethyl acetate, the organic layerwas taken by separation. The ethyl acetate layer was washed with waterand an aqueous solution being saturated with sodium chloride, then driedover anhydrous sodium sulfate. The residue obtained by removal of thesolvent by distillation was purified by use of a thin layerchromatography (eluent: dichloromethane/methanol=30/1), there wasobtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate(91 mg, yield: 87%) as yellow amorphous product.

¹H-NMR (CDCl₃) δ (ppm): 1.20 (3H, s), 2.42 (1H, d, J=14.0 Hz), 2.48-2.77(5H, m, including 2.52, d, J=14.0 Hz) 3.10 (1H, br.s), 3.55 (4H, br.s),4.13 (1H, d, J=14.5 Hz), 4.24 (1H, d, J=14.5 Hz), 4.78 (2H, d, J=6.0Hz), 6.40 (1H, td, J=6.0, 16.0 Hz), 6.66 (1H, d, J=16.0 Hz), 7.46 (1H,t, J=8.0 Hz), 7.49 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0 Hz), 7.67 (1H,dd, J=1.0, 8.0 Hz), 7.80 (1H, dd, J=1.0, 8.0 Hz), 7.97 (1H, s).

Reference Example 24 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrobenzenesulfonyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate

N,N-Dimethylformamide (0.18 ml) solution of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzenesulfonyl)imidazole(36 mg) and 3-(4-trifluoromethylphenyl)-2-propenylpiperazin-1-carboxylate (34 mg) was stirred at 60° C. for 1 day. To thereaction mixture was added water and ethyl acetate, the organic layerwas taken by separation. The ethyl acetate layer was washed with waterand an aqueous solution being saturated with sodium chloride, then driedover anhydrous sodium sulfonate. The residue obtained by removal of thesolvent by distillation was purified by use of a thin layerchromatography (eluent: dichloromethane/methanol=30/1), there wasobtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrobenzenesulfonyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate(45 mg, yield: 67%) as pale yellow amorphous product.

¹H-NMR (CDCl₃) δ (ppm): 1.21 (3H, s), 2.44 (1H, d, J=14.0 Hz), 2.53-2.81(5H, m, including 2.62, d, J=14.0 Hz) 3.40 (1H, br.s), 3.56 (4H, br.s),4.54 (2H, s), 4.79 (2H, d, J=6.0 Hz), 6.40 (1H, td, J=6.0, 16.0 Hz),6.66 (1H, d, J=16.0 Hz), 7.49 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0 Hz),8.13 (1H, s), 8.29 (2H, d, J=9.0 Hz), 8.46 (2H, d, J=9.0 Hz).

In the said reaction, further cyclized3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]-oxazol-2-yl)methylpiperazin-1-carboxylate(7 mg, yield: 14%) was also obtained.

Reference Example 25 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate

To N,N-dimethylformamide (1 ml) solution of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate(100 mg) was added sodium tert-butoxide (19 mg) at 0° C., and stirred atthe same temperature for 20 minutes. To the reaction mixture was addedwater and ethyl acetate, the organic layer was taken by separation. Theethyl acetate layer was washed with an aqueous solution of 5% potassiumcarbonate, water, and an aqueous solution being saturated with sodiumchloride, then dried over anhydrous sodium sulfate. The residue obtainedby removal of the solvent by distillation was purified by use of a basicsilica gel chromatography (eluent: dichloroethane/ethyl acetate=9/1) anda silica gel column chromatography (eluent: dichloromethane/ethylacetate/methanol=20/20/1), there was obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate(40 mg, yield: 54%) as yellow amorphous product.

Reference Example 26 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate

To N,N-dimethylformamide (0.9 ml) solution of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate(89 mg) was added sodium tert-butoxide (16 mg) at 0° C., and stirred atthe same temperature for 30 minutes. To the reaction mixture was addedwater and ethyl acetate, the organic layer was taken by separation. Theethyl acetate layer was washed with an aqueous solution of 5% potassiumcarbonate, water, and an aqueous solution being saturated with sodiumchloride, then dried-over anhydrous sodium sulfate. The residue obtainedby removal of the solvent by distillation was purified by use of a thinlayer chromatography (eluent: dichloromethane/ethylacetate/methanol=15/15/1), there was obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-[(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-yl)methyl]piperazin-1-carboxylate(38 mg, yield: 59%) as pale yellow amorphous product.

Reference Example 27 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate

To N,N-dimethylformamide (0.9 ml) solution of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate(89 mg) was added sodium tert-butoxide (16 mg) at 0° C., and stirred atthe same temperature for 30 minutes. To the reaction mixture was addedwater and ethyl acetate, the organic layer was taken by separation. Theethyl acetate layer was washed with an aqueous solution of 5% potassiumcarbonate, water, and an aqueous solution being saturated with sodiumchloride, then dried over anhydrous sodium sulfate. The residue obtainedby removal of the solvent by distillation was purified by use of a thinlayer chromatography (eluent: dichloromethane/ethylacetate/methanol=15/15/1), there was obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate(32 mg, yield: 51%) as pale yellow amorphous product.

Reference Example 28 Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate

To N,N-dimethylformamide (0.5 ml) solution of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrobenzenesulfonyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate(45 mg) was added sodium tert-butoxide (8 mg) at 0° C., and stirred atthe same temperature for 30 minutes. To the reaction mixture was addedwater and ethyl acetate, the organic layer was taken by separation. Theethyl acetate layer was washed with an aqueous solution of 5%-potassiumcarbonate, water, and an aqueous solution being saturated with sodiumchloride, then dried over anhydrous sodium sulfate. The residue obtainedby removal of the solvent by distillation was purified by use of a thinlayer chromatography (eluent: dichloromethane/ethyl acetate/methanol15/15/1), there was obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate(13 mg, yield: 39%) as pale yellow amorphous product.

Reference Example 29 Preparation of(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg) wasdissolved in N,N-dimethylformamide (3 ml), then under ice-coolingcondition, sodium hydride (86 mg) was added, the reaction mixture wasstirred at 70-75° C. for 20 minutes. The reaction mixture wasice-cooled, a solution prepared by dissolving(R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg)prepared in example 6 in N,N-dimethylformamide (3 ml) was added andstirred at 70-75° C. for 20 minutes. The reaction mixture was turnedback to a room temperature, ice-water (25 ml) was added, and extracted 3times with dichloromethane (50 ml). The organic layers were combined,after being washed with water 3 times, the organic layer was dried overanhydrous magnesium sulfate. After being filterated under a reducedpressure, the filtrate was concentrated, and the obtained residue waspurified by use of a silica gel column chromatography (eluent:dichloromethane/ethyl acetate=3/1). Recrystallized from ethylacetate/diisopropyl ether, there was obtained(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole(343 mg, yield: 33%) as pale yellow powder product.

Reference Example 30 (1) Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate

Mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole(2.04 g) prepared in example 6,3-(4-trifluoromethylphenyl)-2-propenylpiperazin-1-carboxylate (2.69 g) and N,N-dimethylformamide (10 ml) wasstirred at 50° C. for 20 hours. The reaction mixture was turned back toa room temperature, water (45 ml) was added, then extracted twice withethyl acetate (15 ml). The organic layers were combined together, washedwith water 3 times, dried over anhydrous sodium sulfate. After beingfiltrated under a reduced pressure, the residue thus obtained waspurified by use of a silica gel column chromatography (eluent:n-hexane/ethyl acetate=1/2), there was obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate(3.77 g, yield: 84%).

¹H-NMR (CDCl₃) δ(ppm): 1.16 (3H, s), 2.36 (1H, d, J=14.0 Hz), 2.43-2.76(5H, m), 3.21 (1H, s), 3.41-3.57 (4H, m), 4.01 (2H, s), 4.78 (2H, dd,J=1.0 Hz, 6.1 Hz), 6.29-6.43 (1H, m), 6.66 (1H, d, J=16.0 Hz), 7.48 (2H,d, J=8.3 Hz), 7.58 (2H, d, J=8.3 Hz), 8.10 (1H, s).

(2) Preparation of3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate

3-(4-Trifluoromethylphenyl)-2-propenyl(S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropenyl]piperazin-1-carboxylate(3.5 g) was dissolved in N,N-dimethylformamide (10.5 ml), underice-cooling condition, sodium hydride (316 mg) was added, the reactionmixture was stirred at the same temperature for 1.5 hours. Ethyl acetate(3.5 ml) and water (24.5 ml) were added to the reaction mixture, andstirred for 30 minutes. Separated out crystals were collected byfiltration, then washed with water. The crystals were purified by use ofa silica gel column chromatography (eluent: ethyl acetate).Recrystallized from 2-propanol/water, there was obtained3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine(2.07 g, yield: 69%) as pale yellow powder product.

Reference Example 31 Preparation of(R)-(−)-1-(tert-butylmethylsilanyloxy)-3-chloropropan-2-ol

To N,N-dimethylformamide (40 ml) solution of(R)-(−)-3-chloro-1,2-propanediol (7 g), under ice-cooling and stirringcondition, were added tert-butyldimethylchlorosilane (10.6 g) andimidazole (5.2 g), then stirred at a room temperature overnight.Ice-water (120 ml) was added to the reaction mixture, and extracted withethyl acetate (50 ml) 3 times, the extracts were combined together andwashed with an aqueous solution being saturated with sodium chloride,then dried over anhydrous magnesium sulfate. After being filtrated undera reduced pressure, the filtrate was concentrated, there was obtained(R)-(−)-1-(tert-butyldimethylsilanyloxy)-3-chloropropan-2-ol (13.24 g,yield: 92.4%) as colorless liquid product.

¹H-NMR (CDCl₃) δ(ppm): 0.09 (6H, s), 0.91 (9H, s), 3.75-3.62 (2H, m),3.67-3.72 (2H, m), 3.81-3.89 (1H, m).

Reference Example 32 Preparation of1-(tert-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane

(R)-(−)-1-(tert-Butyldimethylsilanyloxy)-3-chloropropan-2-ol (11.19 g)prepared in reference example 31 was dissolved in dichloromethane (20ml), then 3,4-dihydro-2H-pyran (5.87 ml) and pyridiniump-toluenesulfonate (catalytic amount) were added, then the reactionmixture was stirred at a room temperature overnight. The reactionmixture was concentrated under a reduced pressure, the residue waspurified by use of a silica gel column chromatography (eluent:n-hexane/ethyl acetate=20/1), there was obtained1-(t-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane(14.14 g, yield: 92.0%) as colorless liquid product.

¹H-NMR (CDCl₃) δ (ppm): 0.07 (6H, s), 0.89 (9H, s), 1.45-1.89 (6H, m),3.43-4.03 (7H, m), 4.76-4.80 (1H, m).

Reference Example 33 Preparation of(3R)-tetrahydropyranyloxy-6-nitro-2H-3,4-dihydro[2,1-b]imidazopyran

To N,N-dimethylformamide (60 ml) solution of2-bromo-1-[3-hydroxy-2-(tetrahydropyran-2-yloxy)propyl]-4-nitro-1H-imidazole(8.51 g) prepared in example 29 was added sodium hydride (1.07 g) underice-cooling and stirring condition, then the reaction mixture wasstirred at a room temperature for 3 hours. Ice-water was added to thereaction mixture, then extracted twice with ethyl acetate (200 ml), andthe extract was washed with an aqueous solution being saturated withsodium chloride, then dried over anhydrous magnesium sulfate. Afterbeing filtrated under a reduced pressure, the filtrate was concentratedunder a reduced pressure. The residue thus obtained was purified by useof a silia gel column chromatography (eluent: dichloromethane/ethylacetate=10/1), crystallized from dichloromethane-diisopropyl ether,there was obtained(3R)-tetrahydropyranyloxy-6-nitro-2H-3,4-dihydro[2,1-b]imidazopyran (3.3g, yield: 50%) as white powdery product.

Example 8 Preparation of 2-chloro-4-nitroimidazole

Nitronium tetrafluoroborate (398 mg) was dissolved in nitromethane (5ml), next 2-chloroimidazole (205 mg) was added, the reaction mixture wasstirred at a room temperature for 1 hour. The reaction mixture wasneutralized with an aqueous solution of sodium hydrogencarbonate, thenwas turned back to acidic by adding hydrochloric acid, the separated2-chloro-4-nitroimidazole (137 mg) was collected by filtration. Thefiltrate was extracted with ethyl acetate-methanol, the solid matterobtained from the organic layer was triturated with diethyl ether,2-chloro-4-nitroimidazole (103 mg) was obtained. The sum of 240 mg(yield: 81.3%) of 2-chloro-4-nitroimidazole was obtained as colorlesssolid product. ¹H-NMR (DMSO-d₆) δ(ppm): 8.44 (1H, s), 14.19 (1H, bs).

Example 9 Preparation of 2-chloro-4-nitroimidazole

2-Chloro-5-iodo-4-nitroimidazole (273 mg) was dissolved in ethanol (5ml), then triethylamine (420 μl) and 10% palladium-carbon (27 mg) wereadded, the reaction mixture was subjected to hydrogenation at a roomtemperature under normal pressure for 3 hours, there was obtained2-chloro-4-nitroimidazole (124 mg, yield: 84.1%) as colorless solidproduct.

¹H-NMR (DMSO-d₆) δ(ppm): 8.44 (1H, s), 14.19 (1H, bs).

Example 10 Preparation of 2-chloro-4-nitroimidazole

2-Chloro-5-iodo-4-nitroimidazole (273 mg) was dissolved in ethanol (5ml), then triethylamine (420 μl) and 20% palladium hydroxide-carbon (27mg) were added, the reaction mixture was subjected to hydrogenation at aroom temperature under normal pressure for 5 hours, there was obtained2-chloro-4-nitroimidazole (123 mg, yield: 83.4%) as colorless solidproduct.

¹H-NMR (DMSO-d₆) δ(ppm): 8.44 (1H, s), 14.19 (1H, bs).

Example 11 Preparation of 2-chloro-4-nitroimidazole

2-Chloro-5-iodo-4-nitroimidazole (545 mg) was dissolved in ethanol (10ml), then triethylamine (840 μl) and 10% palladium-carbon (54 mg) wereadded, the reaction mixture was subjected to hydrogenation at hydrogenpressure of 4 kg/cm2 by use of Pearl reduction equipment, there wasobtained 2-chloro-4-nitroimidazole (246 mg, yield: 83.4%) as colorlesssolid matter.

¹H-NMR (DMSO-d₆) δ(ppm): 8.44 (1H, s), 14.19 (1H, bs).

Example 12 Preparation of 2-chloro-4-nitroimidazole

2-Chloro-5-iodo-4-nitroimidazole (273 mg) was suspended in 1,4-dioxane(5 ml), then tetra-n-butyl ammonium borohydride (515 mg) was added, thereaction mixture was heated and refluxed for 10 hours. Then dilutedhydrochloric acid was added to the reaction mixture, and extracted withethyl acetate. The organic layer was treated with concentratedhydrochloric acid, the separated matters were collected by filtration.The filtrate was extracted with ethyl acetate, the separated matterobtained from the organic layer was combined together with thepreviously obtained solid matter and purified by use of a silica gelcolumn chromatography (eluent: n-hexane/ethylacetate=3/1 to 2/1), therewas obtained 2-chloro-4-nitroimidazole (107 mg, yield: 72.5%).

¹H-NMR (DMSO-d₆) δ(ppm): 8.44 (1H, s), 14.19 (1H, bs).

Example 13 Preparation of 4-nitro-2-(4-nitrophenylthio) imidazole

Chlorobenzene (5 ml) solution of 1-nitro-2-(4-nitrophenylthio)imidazole(250 mg) was stirred at 85-95° C. for 20 minutes. The residue obtainedby concentration of the reaction mixture was purified by use of a silicagel column chromatography (eluent:dichloromethane-dichloromethane/methanol=50/1) and a thin layerchromatography (eluent: dichloromethane/methanol=10/1), there wasobtained 4-nitro-2-(4-nitrophenylthio)imidazole (108 mg, yield: 44%) asyellow powder product.

¹H-NMR (DMSO-d₆) δ(ppm): 7.44 (2H, d, J=9.0 Hz), 8.18 (2H, d, J=9.0 Hz),8.63 (1H, s), 14.24 (1H, br.s).

Example 14 Preparation of 4-nitro-2-(2-nitrophenylthio) imidazole

Chlorobenzene (10 ml) suspension of1-nitro-2-(2-nitrophenylthio)imidazole (464 mg) was stirred at 70-80° C.for 30 minutes. The residue obtained by concentration of the reactionmixture was purified by use of a silica gel column chromatography(eluent: dichloromethane/ethyl acetate=19/1), there was obtained4-nitro-2-(2-nitrophenylthio)imidazole (223 mg, yield: 49%) as yellowpowder product.

¹H-NMR (DMSO-d₆) δ(ppm): 6.94 (1H, dd, J=1.3, 8.0 Hz), 7.51 (1H, dt,J=1.3, 8.0 Hz), 7.67 (1H, dt, J=1.3, 8.0 Hz), 8.31 (1H, dd, J=1.3, 8.0Hz) 8.66 (1H, s) 14.24 (1H, br.s).

Example 15 Preparation of2-(2-chloro-6-nitrophenylthio)-4-nitroimidazole

Chlorobenzene (6 ml) solution of2-(2-chloro-6-nitrophenylthio)-1-nitroimidazole (300 mg) was stirred at70-80° C. for 30 minutes. The residue obtained by concentration of thereaction mixture was purified by use of a silica gel columnchromatography (eluent: dichloromethane/ethyl acetate 19/1), there wasobtained 4-nitro-2-(2-chloro-6-nitrophenylthio)imidazole (138 mg, yield:46%) as yellow powder product.

¹H-NMR (DMSO-d₆) δ(ppm): 7.75 (1H, t, J=8.0 Hz), 7.97 (1H, dd, J=1.0,8.0 Hz), 8.07 (1H, dd, J=1.0, 8.0 Hz), 8.44 (1H, s), 13.82 (1H, br.s).

Example 16 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole

4-Nitro-2-(4-nitrophenylthio)imidazole (500 mg) andN,N-dimethylformamide (1.6 ml) suspension of2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (513 mg), potassiumcarbonate (337 mg) and cesium fluoride (57 mg) were stirred at a roomtemperature for 1.5 days. Water and ethyl acetate were added to thereaction mixture and the organic layer was taken by separation. Theethyl acetate layer was washed with water and an aqueous solution beingsaturated with sodium chloride, then dried over anhydrous sodiumsulfate. The residue obtained by removal of the solvent by distillationwas purified by use of a basic silica gel column chromatography (eluent:n-hexane/ethyl acetate=13/7 to 11/9), there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole(456 mg, yield: 74%) as pale yellow powder product.

¹H-NMR (CDCl₃) δ(ppm): 1.28 (3H, s), 2.54 (1H, d, J=3.5 Hz), 2.72 (1H,d, J=3.5 Hz), 4.04 (1H, d, J=14.5 Hz), 4.51 (1H, d, J=14.5 Hz), 7.42(2H, d, J=9.0 Hz), 8.07 (1H, s), 8.17 (2H, d, J=9.0 Hz).

Example 17 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(2-nitrophenylthio)imidazole

4-Nitro-2-(2-nitrophenylthio)imidazole (100 mg) andN,N-dimethylformamide (0.5 ml) suspension of2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (119 mg), potassiumcarbonate (71 mg) and cesium fluoride (11 mg) were stirred at a roomtemperature for 3.5 days. Water and ethyl acetate were added to thereaction mixture and the organic layer was taken by separation. Theethyl acetate layer was washed with water and an aqueous solution beingsaturated with sodium chloride, then dried over anhydrous sodiumsulfate. The residue obtained by removal of the solvent by distillationwas purified by use of a basic silica gel column chromatography (eluent:n-hexane/ethyl acetate=11/9 to 1/1), then there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(2-nitrophenylthio)imidazole(102 mg, yield: 79%) as yellow powder product.

¹H-NMR (CDCl₃) δ(ppm): 1.26 (3H, s), 2.54 (1H, d, J=4.0 Hz), 2.72 (1H,d, J=4.0 Hz), 3.98 (1H, d, J=14.5 Hz), 4.51 (1H, d, J=14.5 Hz), 6.95(1H, dd, J=1.0, 8.0 Hz), 7.40 (1H, dt, J=1.0, 8.0 Hz), 7.51 (1H, dt,J=1.0, 8.0 Hz), 8.14 (1H, s), 8.29 (1H, dd, J=1.0, 8.0 Hz).

Example 18 Preparation of(R)-2-(2-chloro-6-nitrophenylthio)-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole

2-(2-Chloro-6-nitrophenylthio)-4-nitroimidazole (113 mg) andN,N-dimethylformamide (0.5 ml) suspension of2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (119 mg), potassiumcarbonate (71 mg) and cesium fluoride (11 mg) were stirred at a roomtemperature for 3.5 days. Water and ethyl acetate were added to thereaction mixture and the organic layer was taken by separation. Theethyl acetate layer was washed with water and an aqueous solution beingsaturated with sodium chloride, then dried over anhydrous sodiumsulfate. The residue obtained by removal of the solvent by distillationwas purified by use of a basic silica gel column chromatography (eluent:n-hexane/ethyl acetate=11/9 to 1/1), then there was obtained(R)-2-(2-chloro-6-nitrophenylthio)-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole(85 mg, yield: 61%) as yellow powdery product.

¹H-NMR (CDCl₃) δ(ppm): 1.43 (3H, s), 2.56 (1H, d, J=4.0 Hz), 2.76 (1H,d, J=4.0 Hz), 4.20 (1H, d, J=15.0 Hz), 4.53 (1H, d, J=15.0 Hz), 7.47(1H, t, J=8.0 Hz), 7.68 (1H, dd, J=1.0, 8.0 Hz), 8.82 (1H, dd, J=1.0,8.0 Hz), 7.87 (1H, s).

Example 19 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzenesulfonyl)imidazole

To dichloromethane (4 ml) solution of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole(100 mg) was added m-chloroperbenzoic acid (160 mg) at 0° C., thereaction mixture was stirred at the same temperature for 14 hours. Thereaction mixture was treated by use of a basic silica gel columnchromatography (eluent: dichloromethane) to obtained crude product. Todichloromethane (4 ml) solution of this crude product was addedm-chloroperbenzoic acid (110 mg) at 0° C., then stirred at a roomtemperature for 1 day. This reaction mixture was treated by use of abasic silica gel column chromatography (eluent: dichloromethane), thusobtained crude product was purified by use of a silia gel columnchromatography (eluent: n-hexane/ethyl acetate=1/1), there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzensulfonyl)imidazole(85 mg, yield 77%) as white powder product.

¹H-NMR (CDCl₃) δ(ppm): 1.46 (3H, s), 2.56 (1H, d, J=3.9 Hz), 2.80 (1H,d, J=3.9 Hz), 4.43 (H, d, J=14.7 Hz), 5.03 (1H, d, J=14.7 Hz), 7.94 (1H,s), 8.32 (2H, d, J=9.0 Hz), 8.46 (2H, d, J=9.0 Hz).

Example 20 Preparation of 4-nitro-2-(4-nitrobenzenesulfonyl) imidazole

To dichloromethane (20 ml)-ethanol (20 ml) suspension of4-nitro-2-(4-nitrophenylthio)imidazole (1.0 g) was addedm-chloroperbenzoic acid (2.0 g) at a room temperature, the reactionmixture was stirred at the same temperature for 8 hours. To the reactionmixture was added an aqueous solution of 5% sodium hydrogensulfite, andstirred overnight. Water was added, after being stirred vigorously, theinsoluble matters were collected by filtration. Thus obtained solidmatters were washed with water, then the solid matters were dispersedand washed under refluxing condition in methanol. The insoluble matterswere collected by filtration, thus obtained solid matters were dispersedand washed under the condition similar to the above condition indichloromethane-methanol, then dried, there was obtained4-nitro-2-(4-nitrobenzenesulfonyl)imidazole (919 mg: yield 82%) as whitepowdery product.

¹H-NMR (DMSO-d₆) δ(ppm): 8.25 (2H, d, J=9.0 Hz), 8.48 (2H, d, J=9.0 Hz),8.58 (1H, s).

Example 21 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzenesulfonyl)imidazole

4-Nitro-2-(4-nitrobenzenesulfonyl)imidazole (200 mg) andN,N-dimethylformamide (0.57 ml) suspension of2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (183 mg), potassiumcarbonate (120 mg) and cesium fluoride (20 mg) were stirred at a roomtemperature for 1.5 days. Water and ethyl acetate were added to thereaction mixture, and organic layer was taken by separation. The ethylacetate layer was washed with water and an aqueous solution beingsaturated with sodium chloride, then dried over anhydrous sodiumsulfate. The residue obtained by removal of the solvent by distillationwas purified by use of a silica gel column chromatography (eluent:n-hexane/ethyl acetate=11/9 to 1/1), there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzenesulfonyl)imidazole(76 mg, yield: 31%) as white powdery product.

¹H-NMR (CDCl₃) δ(ppm): 1.46 (3H, s), 2.56 (1H, d, J=3.9 Hz), 2.8.0 (1H,d, J=3.9 Hz), 4.43 (1H, d, J=14.7 Hz), 5.03 (1H, d, J=14.7 Hz), 7.94(1H, s), 8.32 (2H, d, J=9.0 Hz), 8.46 (2H, d, J=9.0 Hz).

Example 22 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole

To chloroform (5 ml) solution of(R)-1-(2-methyl-2-oxiranylmethyl)-2-(4-nitrophenylthio)imidazole (200mg) and tetra-n-butylammonium nitrate (230 mg) was added anhydroustrifluoroacetic acid (0.11 ml) at −20° C., and the reaction mixture wasstirred at −20° C. to 0° C. for 7.5 hours. After being added 1N sodiumhydroxide (2 ml) to the reaction mixture and stirred for 30 minutes,ethyl acetate and water were added, then the organic layer was taken byseparation. The ethyl acetate layer was washed with an aqueous solutionof 5% sodium hydrogensulfite, water and an aqueous solution beingsaturated with sodium chloride, then dried over anhydrous sodiumsulfate. The residue obtained by removal of the solvent by distillationwas purified by use of a thin layer chromatography (eluent:dichloromethane/ethyl acetate=9/1), there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole(15 mg, yield: 6.7%) as yellow amorphous product.

¹H-NMR (CDCl₃) δ(ppm): 1.28 (3H, s), 2.54 (1H, d, J=3.5 Hz), 2.72 (1H,d, J=3.5 Hz), 4.04 (1H, d, J=14.5 Hz), 4.51 (1H, d, J=14.5 Hz), 7.42(2H, d, J=9.0 Hz), 8.07 (1H, s), 8.17 (2H, d, J=9.0 Hz).

Example 23 Preparation of(R)-1-(2-methyl-2-oxiranylmethyl)-2-methylthio-4-nitroimidazole

To chloroform (5 ml) solution of(R)-1-(2-methyl-2-oxiranylmethyl)-2-methylthioimidazole (128 mg) andtetra-n-butylammonium nitrate (230 mg) was added anhydroustrifluoroacetic acid (0.11 ml) at −20° C., and the reaction mixture wasstirred at −20° C. to 0° C. for 5 hours. To the reaction mixture wasadded an aqueous solution of 1N sodium hydroxide (2 ml), after beingstirred for 30 minutes, ethyl acetate and water were added, the organiclayer was taken by separation. The ethyl acetate layer was washed withan aqueous solution of 5% sodium hydrogensulfite, water and an aqueoussolution being saturated with sodium chloride, then dried over anhydroussodium sulfate. The residue obtained by removal of the solvent bydistillation was purified by use of a thin layer chromatography (eluent:n-hexane/ethyl acetate=1/1), there was obtained(R)-1-(2-methyl-2-oxiranylmethyl)-2-methylthio-4-nitroimidazole (13 mg,yield: 8.3%) as pale yellow oily product.

¹H-NMR (CDCl₃) δ (ppm): 1.36 (3H, s), 2.59 (1H, d, J=4.0 Hz), 2.73 (3H,s) 2.74 (1H, d, J=4.0 Hz), 3.92 (1H, d, J=15.0 Hz), 4.23 (1H, d, J=15.0Hz), 7.85 (1H, s).

Example 24 Preparations of1-(2-cyanoethyl)-5-nitro-2-(4-nitrophenylthio)imidazole and1-(2-cyanoethyl)-4-nitro-2-(4-nitrophenylthio)imidazole

To chloroform solution of1-(2-cyanoethyl)-2-(4-nitrophenylthio)imidazole (250 mg) andtetra-n-butylammonium nitrate (333 mg) was added anhydroustrifluoroacetic acid (0.16 ml) at −10° C., then the reaction mixture wasstirred at 0° C. for 6.5 hours. To the reaction mixture was added 1Nsodium hydroxide (2.4 ml), after being stirred for 30 minutes, ethylacetate and water, then the organic layer was taken by liquidseparation. The ethyl acetate was washed with water and an aqueoussolution being saturated with sodium chloride, then dried over anhydroussodium sulfate. The residue obtained by removal of the solvent bydistillation was purified by use of a silica gel column chromatography(eluent: n-hexane/ethyl acetate=3/2 to 11/9 to 2/3), there were obtained1-(2-cyanoethyl)-5-nitro-2-(4-nitrophenylthio)imidazole (36 mg, yield:12%) as yellow oily product and1-(2-cyanoethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (29 mg, yield:10%) as violet oily product.

(1) 5-Nitro compound: ¹H-NMR (CDCl₃) δ(ppm): 2.99 (2H, t, J=6.5 Hz),4.82 (2H, d, J=6.5 Hz), 7.64 (2H, d, J=9.0 Hz), 8.13 (1H, s), 8.24 (2H,d, J=9.0 Hz).

(2) 4-Nitro compound: ¹H-NMR (CDCl₃) δ(ppm): 2.84 (2H, t, J=6.5 Hz),4.43 (2H, t, J=6.5 Hz), 7.43 (2H, d, J=9.0 Hz), 8.09 (1H, s), 8.21 (2H,d, J=9.0 Hz).

Example 25 Preparation of 4-nitro-2-(4-nitrophenylthio)imidazole

To tetrahydrofuran (1 ml) solution of1-(2-cyanoethyl)-5-nitro-2-(4-nitrophenylthio)imidazole (36 mg) wasadded 1,8-diazabicyclo[5.4.0]undecene-7 (0.02 ml) at a room temperature,and stirred at the same temperature for 5 hours. To the reaction mixturewere added 1N hydrochloric acid (0.2 ml), water and ethyl acetate, thenthe organic layer was taken by liquid separation. The ethyl acetatelayer was washed with water and an aqueous solution being saturated withsodium chloride, then dried over anhydrous sodium sulfate. The residueobtained by removal of the solvent by distillation was purified by useof a silica gel column chromatography (eluent: dichloromethane/ethylacetate=4/1), there was obtained 4-nitro-2-(4-nitrophenylthio)imidazole(27 mg, yield 91%) as pale yellow powder product.

¹H-NMR (DMSO-d₆) δ(ppm): 7.44 (2H, d, J=9.0 Hz), 8.18 (2H, d, J=9.0 Hz),8.63 (1H, s), 14.24 (1H, br.s).

Example 26 Preparation of 4-nitro-2-(4-nitrophenylthio)imidazole

To tetrahydrofuran (1 ml) solution of1-(2-cyanoethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (27 mg) wasadded 1,8-diazabicyclo[5.4.0]undecene-7 (0.02 ml) at a room temperature,and stirred at the same temperature for 3 hours. To the reaction mixturewere added 1N hydrochloric acid (0.7 ml), water and ethyl acetate, thenthe organic layer was taken by liquid separation. The ethyl acetatelayer was washed with water and an aqueous solution being saturated withsodium chloride, then dried over anhydrous sodium sulfate. The residueobtained by removal of the solvent by distillation was purified by useof a thin layer chromatography (eluent: dichloromethane/ethylacetate=9/1), there was obtained 4-nitro-2-(4-nitrophenylthio)imidazole(13 mg, yield 58%) as reddish brown powdery product.

¹H-NMR (DMSO-d₆) δ(ppm): 7.44 (2H, d, J=9.0 Hz), 8.18 (2H, d, J=9.0 Hz),8.63 (1H, s), 14.24 (1H, br.s).

Example 27 Preparation of(S)-2-bromo-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole

A suspension of 2-bromo-4-nitroimidazole (100 g),2-methyl-2-oxiranylmethyl(R)-4-nitrobenzenesulfonate (142.4 g),potassium carbonate (93.6 g) and cesium fluoride (15.8 g) inN,N-dimethylformamide (420 ml) was stirred at 35-40° C. for 26 hours.The reaction mixture was poured into water (1.2 liters) and extractedtwice with ethyl acetate (1 liter). Ethyl acetate layers were combinedtogether, after being washed twice with water (1.2 liters), furtherwashed with an aqueous solution being saturated with sodium chloride(800 ml), then dried over anhydrous magnesium sulfate. After beingfiltrated under a reduced pressure, the filtrate was concentrated undera reduced pressure. The residue thus obtained was purified by use of asilica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1),there was obtained(S)-2-bromo-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (112.3 g,yield: 82%) as yellow powdery product.

Melting point: 93.0-94.0° C.

¹H-NMR (CDCl₃) δ(ppm): 1.38 (3H, s), 2.61 (1H, d, J=4.0 Hz), 2.78 (1H,d, J=4.0 Hz), 4.00 (1H, d, J=14.9 Hz), 4.38 (1H, d, J=14.9 Hz), 7.92(1H, s).

Optical purity: 96.4% e.e.

The optical purity was determined by a high performance liquidchromatography (HPLC) under the following conditions.

Column: CHIRALPAK AD (4.6 mmφ×250 mm)

-   -   [manufactured by Daicel Chemical Industries, Inc.]

Moving bed: n-hexane/ethanol=4/1

Flow velocity: 1.0 ml/minute

Detection wave length: 254 nm.

Example 28 Preparation of2-bromo-1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole

2-Bromo-4-nitroimidazole (7.63 g) and1-(tert-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane(12 g) were dissolved in N,N-dimethylformamide (80 ml), then potassiumcarbonate (6.6 g) and sodium iodide (6.3 g) were added thereto, and thereaction mixture was heated and stirred at 110° C. for 12 hours.Ice-water (240 ml) was added, extracted twice with ethyl acetate (150ml), and the extracts were combined together and washed with an aqueoussolution being saturated with sodium chloride (100 ml), then dried overanhydrous magnesium sulfate. After being filtrated under a reducedpressure, the filtrate was concentrated under a reduced pressure. Theresidue obtained was purified by use of a silica gel columnchromatography (eluent: dichloromethane/ethyl acetate=100/1), there wasobtained2-bromo-1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole (12.69 g, yield: 68.7%).

¹H-NMR (CDCl₃) δ(ppm): 0.08 (3H, s), 0.01 (3H, s), 0.91 (4.5H, s), 0.93(4.5H, s), 1.39-1.80 (6H, m), 3.35-4.45 (8.5H, m), 4.65-4.68 (0.5H, m),7.90 (0.5H, s), 8.01 (0.5H, s).

EI (m/z) M⁺=464.

Example 29 Preparation of2-bromo-1-[3-hydroxy-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole

To tetrahydrofuran (120 ml) solution of2-bromo-1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl)-4-nitroimidazole(12.7 g) prepared in Example 28, was added 1M tetra-n-butylammoniumfluoride tetrahydrofuran solution (30 ml) under stirring and ice-coolingcondition, the reaction mixture was stirred at a room temperatureovernight. The reaction mixture was concentrated under a reducedpressure and the residue was diluted with ethyl acetate, washed withwater and an aqueous solution being saturated with sodium chloride.After being dried over anhydrous magnesium sulfate, the residue wasconcentrated under a reduced pressure, thus obtained residue waspurified by use of a silica gel column chromatography (eluent:dichloromethane/ethyl acetate=10/1), there was obtained2-bromo-1-[3-hydroxy-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole(8.51 g, yield: 89%) as colorless liquid product.

¹H-NMR (CDCl₃) δ (ppm): 1.50-1.94 (6H, m), 3.38-4.31 (8.5H, m),4.67-4.71 (0.5H, m), 7.87 (0.5H, s), 8.01 (0.5H, s).

EI (m/z) M⁺=350.

Example 30 Preparation of1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-2-chloro-4-nitroimidazole

Similar to Example 28, the objective compound was synthesized from2-chloro-4-nitroimidazole (2.15 g) and1-(tert-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane(12 g), there was obtained1-[3-(tert-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-2-chloro-4-nitroimidazole(3.03 g, yield: 74.3%) as colorless liquid product.

¹H-NMR (CDCl₃) δ(ppm): 0.08 (3H, s), 0.01 (3H, s), 0.91 (4.5H, s), 0.92(4.5H, s), 1.46-1.80 (6H, m), 3.40-4.45 (8.5H, m), 4.65-4.68 (0.5H, m),7.84 (0.5H, s), 7.96 (0.5H, s).

Example 31 Preparation of2-chloro-1-[3-hydroxy-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole

Similar to Example 29, the objective compound was synthesized from1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-2-chloro-4-nitroimidazole(3.03 g), there was obtained2-chloro-1-[3-hydroxy-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole(1.96 g, yield: 89%) as colorless liquid product.

¹H-NMR (CDCl₃) δ(ppm): 1.44-1.90 (6H, m), 3.37-4.25 (8.5H, m), 4.65-4.70(0.5H, m), 7.84 (0.5H, s), 7.97 (0.5H, s).

1. 1-substituted-4-nitroimidazole compound represented by formula (1),

wherein R is a lower alkoxy group-substituted lower alkyl group, a phenyl-lower alkoxy group-substituted lower alkyl group, a phenyl-lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring, or a group of the formula —CH₂R^(A), wherein R^(A) is a group of the following formula,

and wherein R^(B) is a lower alkyl group; and X is a chlorine atom, a bromine atom or a group of the formula —S(O)n-R¹, wherein n is 0 or an integer of 1 or 2 and R¹ is a phenyl group which may have 1 to 3 substituents, selected from the group consisting of a nitro group, a halogen atom and a lower alkyl group, on the phenyl ring, or a salt thereof. 